RARE DISEASE
Delta-sarcoglycan-related limb-girdle muscular dystrophy R6
Delta-sarcoglycan-related limb-girdle muscular dystrophy R6
Delta-sarcoglycan-related limb-girdle muscular dystrophy R6
Synonyms: Autosomal recessive limb-girdle muscular dystrophy type 2F, Delta-sarcoglycan-related LGMD R6, Delta-sarcoglycanopathy, LGMD due to delta-sarcoglycan deficiency, LGMD type 2F, LGMD2F, Limb-girdle muscular dystrophy due to delta-sarcoglycan deficiency, Limb-girdle muscular dystrophy type 2F
Synonyms: Autosomal recessive limb-girdle muscular dystrophy type 2F, Delta-sarcoglycan-related LGMD R6, Delta-sarcoglycanopathy, LGMD due to delta-sarcoglycan deficiency, LGMD type 2F, LGMD2F, Limb-girdle muscular dystrophy due to delta-sarcoglycan deficiency, Limb-girdle muscular dystrophy type 2F
Synonyms: Autosomal recessive limb-girdle muscular dystrophy type 2F, Delta-sarcoglycan-related LGMD R6, Delta-sarcoglycanopathy, LGMD due to delta-sarcoglycan deficiency, LGMD type 2F, LGMD2F, Limb-girdle muscular dystrophy due to delta-sarcoglycan deficiency, Limb-girdle muscular dystrophy type 2F
Drug discovery
0
drugs
With orphan designations
Overview
Delta-sarcoglycan-related limb-girdle muscular dystrophy R6 (LGMDR6) is an ultra-rare autosomal recessive disorder caused by SGCD mutations, leading to progressive weakness of proximal limb-girdle muscles, cardiomyopathy, and respiratory impairment. Onset typically occurs in childhood, with elevated CK levels, calf hypertrophy, and preserved neurodevelopment. Disease progression often results in loss of ambulation by early adolescence, with cardiac and respiratory complications significantly impacting morbidity and mortality [1][4][10].
Burden
Rapid progression: 60% require wheelchairs by age 12, with frequent hospitalizations for cardiac/respiratory crises [4][10].
Multisystem morbidity: 21.7% develop cardiomyopathy; 17.4% require permanent ventilatory support [4][12].
Mortality: Premature death from respiratory failure or dilated cardiomyopathy despite interventions [1][6].
Therapies
Supportive care: Physiotherapy for contractures, non-invasive ventilation for respiratory insufficiency, and cardiac monitoring/treatment (β-blockers, ACE inhibitors) [3][4].
Gene therapy: Preclinical studies show δ-sarcoglycan replacement improves cardiac/skeletal muscle function in animal models; Phase I human trials remain investigational [2][5][11].
Clinical trials: Focused on sarcoglycan complex restoration and DGC stabilization, though no disease-modifying therapies exist [6][13].
Categories: rare cardiac diseases, rare genetic diseases, rare neurological diseases, rare transplant-related disorders
Research Papers
75 drug discovery papers about Delta-sarcoglycan-related limb-girdle muscular dystrophy R6, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
75 drug discovery papers about Delta-sarcoglycan-related limb-girdle muscular dystrophy R6, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
gene therapies
2025-03-25 | Sarcoglycanopathies: From clinical diagnosis to new promising therapies
The sarcoglycanopathies are a severe form of limb girdle muscular dystrophy caused by mutations in the sarcoglycan genes SGCA, SGCB, SGCG, and SGCD, leading to reduced or absent expression of the alpha-, beta-, gamma-, and delta-sarcoglycan proteins respectively. Most patients develop a severe disease starting in the first decade of life that progresses quickly and eventually leads to a loss of ambulation before the age of 20. However, there is a marked heterogeneity in the prognosis, and several patients develop a milder phenotype. The factors correlating with disease progression are not completely known, but recent data suggest that remaining protein expression can be a key factor. The diagnosis is confirmed by genetic studies, which are sometimes not confirmative in the case of identifying variants of unknown significance or just one variant. New tools to understand the potential pathogenesis of missense variants have been developed; these are helping in the diagnosis of these diseases. Additionally, recent data on muscle MRI have revealed a characteristic pattern of involvement that can also support the diagnosis of the disease. In recent years, data coming from international collaborative studies have allowed an understanding of disease progression; however, this is only through retrospective data. There are no prospective studies collecting longitudinal data on skeletal and respiratory muscle function or cardiac structure and function progression over time which is hampering the development of new drugs in the field. Clinical trials with gene therapy are underway or are being designed in some of the subtypes of sarcoglycanopathies to advance therapeutic management.
2024-05-06 | Advanced therapeutic approaches in sarcoglycanopathies
Sarcoglycanopathies are rare autosomal recessive diseases belonging to the family of limb-girdle muscular dystrophies. They are caused by mutations in the genes coding for α-, β-, γ-, and δ-sarcoglycan. The mutations impair the assembly of a key structural complex, which normally protects the sarcolemma of striated muscle from contraction-derived stress. Although heterogeneous, sarcoglycanopathies are characterized by progressive muscle degeneration, increased serum creatine kinase levels, loss of ambulation often during adolescence, and variable cardio-respiratory impairment. Genetic defects can impair sarcoglycan synthesis or produce a protein that is defective in folding. There is currently no effective treatment available; however, both gene replacement strategy and small molecule-based approaches show great promise and have entered or are starting to enter clinical trials.
2021-07-28 | Sarcoglycanopathies: an update
Sarcoglycanopathies are the most severe forms of autosomal recessive limb-girdle muscular dystrophies (LGMDs), constituting about 10-25% of LGMDs. The clinical phenotype is variable, but onset is usually in the first decade of life. Patients present muscle hypertrophy, elevated CK, variable muscle weaknesses, and progressive loss of ambulation. Four subtypes are known: LGMDR3, LGMDR4, LGMDR5 and LGMDR6, caused, respectively, by mutations in the SGCA, SGCB,SGCG and SGCD genes. Their four coded proteins, α-SG, ß-SG, λ-SG and δ-SG are part of the dystrophin-glycoprotein complex (DGC) present in muscle sarcolemma, which acts as a linker between the cytoskeleton of the muscle fiber and the extracellular matrix, providing mechanical support to the sarcolemma during myofiber contraction. Many different mutations have already been identified in all the sarcoglycan genes, with a predominance of some mutations in different populations. The diagnosis is currently based on the molecular screening for these mutations. Therapeutic approaches include the strategy of gene replacement mediated by a vector derived from adeno-associated virus (AAV). Pre-clinical studies have shown detectable levels of SG proteins in the muscle, and some improvement in the phenotype, in animal models. Therapeutic trials in humans are ongoing.
2019-05-10 | An AAV-SGCG Dose-Response Study in a γ-Sarcoglycanopathy Mouse Model in the Context of Mechanical Stress
Sarcoglycanopathies are rare autosomic limb girdle muscular dystrophies caused by mutations in one of the genes coding for sarcoglycans. Sarcoglycans form a complex, which is an important part of the dystrophin-associated glycoprotein complex and which protects the sarcolemma against muscle contraction-induced damage. Absence of one of the sarcoglycans on the plasma membrane reduces the stability of the whole complex and perturbs muscle fiber membrane integrity. There is currently no curative treatment for any of the sarcoglycanopathies. A first clinical trial to evaluate the safety of a recombinant AAV2/1 vector expressing γ-sarcoglycan using an intramuscular route of administration showed limited expression of the transgene and good tolerance of the approach. In this report, we undertook a dose-effect study in mice to evaluate the efficiency of an AAV2/8-expressing γ-sarcoglycan controlled by a muscle-specific promoter with a systemic mode of administration. We observed a dose-related efficiency with a nearly complete restoration of gamma sarcoglycan (SGCG) expression, histological appearance, biomarker level, and whole-body strength at the highest dose tested. In addition, our data suggest that a high expression threshold level must be achieved for effective protection of the transduced muscle, while a suboptimal transgene expression level might be less protective in the context of mechanical stress. Sarcoglycanopathies are rare autosomic limb girdle muscular dystrophies caused by mutations in one of the genes coding for sarcoglycans. Sarcoglycans form a complex, which is an important part of the dystrophin-associated glycoprotein complex and which protects the sarcolemma against muscle contraction-induced damage. Absence of one of the sarcoglycans on the plasma membrane reduces the stability of the whole complex and perturbs muscle fiber membrane integrity. There is currently no curative treatment for any of the sarcoglycanopathies. A first clinical trial to evaluate the safety of a recombinant AAV2/1 vector expressing γ-sarcoglycan using an intramuscular route of administration showed limited expression of the transgene and good tolerance of the approach. In this report, we undertook a dose-effect study in mice to evaluate the efficiency of an AAV2/8-expressing γ-sarcoglycan controlled by a muscle-specific promoter with a systemic mode of administration. We observed a dose-related efficiency with a nearly complete restoration of gamma sarcoglycan (SGCG) expression, histological appearance, biomarker level, and whole-body strength at the highest dose tested. In addition, our data suggest that a high expression threshold level must be achieved for effective protection of the transduced muscle, while a suboptimal transgene expression level might be less protective in the context of mechanical stress.
2019-03-01 | Various effects of AAV9-mediated βARKct gene therapy on the heart in dystrophin-deficient (mdx) mice and δ-sarcoglycan-deficient (Sgcd-/-) mice
So far effective strategies to treat cardiomyopathy in patients with muscular dystrophies are still not clearly defined. Previously, treatment with β-blockers showed beneficial effects on the development of cardiomyopathy in dystrophin-deficient (mdx) mice, but not in δ-sarcoglycan-deficient (Sgcd-/-) mice. We therefore aimed to study a more specific approach to target maladaptive β-adrenergic signalling in these mice. It has been shown that lowering cardiac G-protein-coupled-receptor-kinase-2 (GRK2) activity with βARKct expression, a peptide inhibitor of protein-coupled-receptor-kinase-2 (GRK2), results in improvement of heart failure in several different animal models. We therefore investigated whether adeno-associated virus type 9 (AAV9)-mediated gene delivery of βARKct, could ameliorate cardiac pathology in mdx and Sgcd-/- mice. We found that long-term treatment with AAV9- βARKct-cDNA with a cardiac-specific promoter significantly improves left ventricular systolic function and reduces myocardial hypertrophy in mdx mice, whereas only mild beneficial effects on cardiac function is observed in Sgcd-/- mice. Interestingly, in contrast to mdx mice neither GRK2 nor nuclear-factor-kappaB (NFκB) were upregulated in Sgcd-/- mice. Taken together, effectiveness of AAV-mediated βARKct therapy may vary between different genetic mutations and presumably depend on the state of adrenergic dysregulation mediated through the upregulation of GRK2.
small molecules
2026-05-19 | The flavanol (-)-epicatechin induced different histological features and myogenic protein levels in triceps, gastrocnemius and plantaris of δ-sarcoglycan-deficient mice.
Limb-girdle muscular dystrophies (LGMD) exhibit a wide range of disease severity, affecting various parts of the skeletal muscle to varying degrees. This may be associated with differences in the degeneration and regeneration processes in different muscles. We previously reported that muscles with different metabolic characteristics showed distinct levels of proteins involved in the muscle regeneration process in δ-sarcoglycan-deficient mice, a model for LGMDR6. These phenomena may be relevant to test potential therapeutic compounds in myopathies. In this study, we analyzed the effect of (-)-epicatechin (Epi), a flavanol enriched in cacao that has shown beneficial effects in skeletal muscle, in different muscles of the δ-sarcoglycan-deficient mice. Histochemical analysis showed that dystrophic triceps and gastrocnemius had a higher level of fibrosis than plantaris, and Epi reduced this. In addition, Epi increased the cross-sectional area of dystrophic triceps fibers, which was associated with a higher fusion index. In contrast, Epi reduced the index fusion in dystrophic plantaris. Western blot analysis demonstrates that Epi increases protein levels of Pax7, β-catenin, and myogenin in the dystrophic triceps and increases protein levels of β-catenin and myogenin in the gastrocnemius. In contrast, in the plantaris, none of the protein levels was modified. All these results suggest that muscles with different metabolic characteristics and physiological demands could respond differentially to pharmacological therapies in dystrophic muscles.
2026-05-06 | (-)-Epicatechin modulates skeletal muscle inflammatory response in a mouse model of Limb-Girdle Muscular Dystrophy 2F
Abstract Skeletal muscle possesses remarkable regenerative capacity. However, in limb-girdle muscular dystrophy-2F (LGMD2F), this capacity is compromised by persistent innate immune activation, whose transcriptional landscape remains unexplored. In parallel, (-)-Epicatechin has emerged as a promising compound with beneficial effects on muscle and notable anti-inflammatory properties. We therefore used (-)-Epicatechin treatment to test whether it can alleviate LGMD2F-associated transcriptional and immune dysregulation. Here we provide the first transcriptomic characterization of LGMD2F using the Sgcd ⁻/⁻ mouse model, along with the first RNA-sequencing-based evaluation of (-)-Epicatechin treatment. We profiled two functionally distinct muscles — the soleus and EDL — through bulk RNA-sequencing coupled with immune cell-deconvolution. Sgcd ⁻/⁻ muscles exhibited marked transcriptional dysregulation, more pronounced in the soleus and associated with enhanced innate immune signaling. (-)-Epicatechin induced a muscle- and genotype-dependent transcriptional response: in wild-type animals, the EDL displayed the highest number of differentially expressed transcripts, whereas in Sgcd ⁻/⁻ mice, the soleus showed the most prominent response. This shift was accompanied by downregulation of Toll-like receptor and RIG-I-like receptor pathways, along with suppression of NF-κB2 and interferon-stimulated genes. Together, these findings identify innate immune overactivation as a central feature of LGMD2F and reveal (-)-Epicatechin as a context-dependent modulator of muscle-specific transcriptional responses.
2025-03-07 | Dysregulated ATX-LPA and YAP/TAZ signaling in dystrophic Sgcd-/- mice with early fibrosis and inflammation.
Sarcoglycanopathies are muscle dystrophies caused by mutations in the genes encoding sarcoglycans (α, β, γ, and δ) that can destabilize the dystrophin-associated glycoprotein complex at the sarcolemma, leaving muscle fibers vulnerable to damage after contraction, followed by inflammatory and fibrotic responses and resulting in muscle weakness and atrophy. Two signaling pathways have been implicated in fibrosis and inflammation in various tissues: autotaxin/lysophosphatidic acid (ATX-LPA) and yes-associated protein 1/transcriptional co-activator with PDZ-binding motif (YAP/TAZ). LPA, synthesized by ATX, can act as a pleiotropic molecule due to its multiple receptors. Two Hippo pathway effectors, YAP/TAZ, can be dephosphorylated by LPA and translocated to the nucleus. They induce several target genes, such as CCN2/CTGF, involved in fibrosis and inflammation. However, no detailed characterization of these processes or whether these pathways change early in the development of sarcoglycanopathy has been evaluated in skeletal muscle. Using the δ-sarcoglycan knockout mouse model (Sgcd-/-), we investigated components of these pathways, inflammatory and fibrotic markers, and contractile properties of different skeletal muscles (triceps-TR, gastrocnemius-GST, diaphragm-DFG, tibialis anterior-TA, and extensor digitorum longus-EDL) at one and two months of age. We found that Sgcd-/- mice show early dystrophic features (fiber damage/necrosis, centrally nucleated fibers, inflammatory infiltrate, and regenerated fibers) followed by later fiber size reduction in TR, GST, and DFG. These changes are concomitant with an early inflammatory and fibrotic response in these muscles. Sgcd-/- mice also have early impaired force generation in the TA and EDL, and resistance to mechanical damage in the EDL. In addition, an early dysregulation of the ATX-LPA axis and the YAP/TAZ signaling pathway in the TR, GST, and DFG was observed in these mice. The ATX-LPA axis and the YAP/TAZ signaling pathway, which are involved in inflammation and fibrosis, are dysregulated in skeletal muscle from an early age in Sgcd-/- mice. These changes are concomitant with a fibrotic and inflammatory response in these mice. Unraveling the role of the LPA axis and YAP/TAZ in sarcoglycanopathy holds great promise for improving our understanding of disease pathogenesis and identifying novel therapeutic targets for this currently incurable group of muscle disorders.
2023-05-29 | The Role of P2X7 Purinoceptors in the Pathogenesis and Treatment of Muscular Dystrophies
Muscular dystrophies are inherited neuromuscular diseases, resulting in progressive disability and often affecting life expectancy. The most severe, common types are Duchenne muscular dystrophy (DMD) and Limb-girdle sarcoglycanopathy, which cause advancing muscle weakness and wasting. These diseases share a common pathomechanism where, due to the loss of the anchoring dystrophin (DMD, dystrophinopathy) or due to mutations in sarcoglycan-encoding genes (LGMDR3 to LGMDR6), the α-sarcoglycan ecto-ATPase activity is lost. This disturbs important purinergic signaling: An acute muscle injury causes the release of large quantities of ATP, which acts as a damage-associated molecular pattern (DAMP). DAMPs trigger inflammation that clears dead tissues and initiates regeneration that eventually restores normal muscle function. However, in DMD and LGMD, the loss of ecto-ATPase activity, that normally curtails this extracellular ATP (eATP)-evoked stimulation, causes exceedingly high eATP levels. Thus, in dystrophic muscles, the acute inflammation becomes chronic and damaging. The very high eATP over-activates P2X7 purinoceptors, not only maintaining the inflammation but also tuning the potentially compensatory P2X7 up-regulation in dystrophic muscle cells into a cell-damaging mechanism exacerbating the pathology. Thus, the P2X7 receptor in dystrophic muscles is a specific therapeutic target. Accordingly, the P2X7 blockade alleviated dystrophic damage in mouse models of dystrophinopathy and sarcoglycanopathy. Therefore, the existing P2X7 blockers should be considered for the treatment of these highly debilitating diseases. This review aims to present the current understanding of the eATP-P2X7 purinoceptor axis in the pathogenesis and treatment of muscular dystrophies.
2019-06-26 | SIRT1 deficiency interferes with membrane resealing after cell membrane injury
Activation of SIRT1, an NAD+-dependent protein deacetylase, ameliorates muscular pathophysiology of δ-sarcoglycan-deficient TO-2 hamsters and dystrophin-deficient mdx mice. We found that SIRT1 was highly expressed beneath the cellular membranes of muscle cells. To elucidate functional roles of SIRT1 on muscles, skeletal muscle-specific SIRT1 knockout mice (SIRT1-MKO) were generated. SIRT1-MKO mice showed muscular pathology similar to mild muscular dystrophies with increased numbers of centrally nucleated small myofibers and decreased numbers of middle-sized (2000–3001 μm2) myofibers compared to those of wild-type (WT) mice. Accordingly, SIRT1-MKO mice showed significantly decreased exercise capacity in treadmill and inverted hanging tests with higher levels of serum creatine kinase activities compared with those in WT mice. Evans blue dye uptake after exercise was greater in the muscles of SIRT1-MKO than those of WT mice, suggesting membrane fragility in SIRT1-MKO mice. Because SIRT1 was dominantly localized beneath the membranes of muscular cells, SIRT1 may have a new role in the membranes. We found that levels of fluorescent FM1-43 dye intake after laser-induced membrane disruption in C2C12 cells were significantly increased by SIRT1 inhibitors or Sirt1-siRNA compared with those of control cells. Inhibition of SIRT1 or SIRT1-knockdown severely disturbed the dynamic aggregation of membrane vesicles under the injured site but did not affect expression levels of membrane repair proteins. These data suggested that SIRT1 had a critical role in the resealing of membrane-ruptured muscle cells, which could affect phenotypes of SIRT1-MKO mice. To our knowledge, this report is the first to demonstrate that SIRT1 affected plasma-membrane repair mechanisms.
proteins
2025-01-22 | Sarcoglycans are enriched at the neuromuscular junction in a nerve-dependent manner
Abstract Sarcoglycanopathies are heterogeneous proximo-distal diseases presenting severe muscle alterations. Although there are 6 different sarcoglycan isoforms, sarcoglycanopathies are caused exclusively by mutations in genes coding for one of the four sarcoglycan transmembrane proteins (alpha, beta, gamma and delta) forming the sarcoglycan complex (SGC) in skeletal and cardiac muscle. Little is known about the different roles of the SGC beyond the dystrophin glycoprotein complex (DGC) structural role. Here, we show that SGC proteins are enriched at the post-synaptic membrane of neuromuscular junctions (NMJs). Using a mouse model lacking the beta-sarcoglycan subunit, we describe for the first time that the loss of the SGC in the NMJ area results in alterations of pre- and postsynaptic membrane, as well as a significant reduction of membrane potential. Moreover, using different denervated wild-type mouse models, we demonstrate that nerve presence precedes the sarcoglycan enrichment at NMJ, suggesting a nerve-dependent sarcoglycan expression. Altogether, our findings suggest that pathological decline should no longer be understood only in terms of sarcolemma damage but also in terms of sarcoglycans’ participation in the NMJ. Henceforth, our work paves the way for the identification of new mechanisms involving sarcoglycans and new approaches for the treatment of sarcoglycanopathies.
2024-06-27 | Thrombospondin-4 deletion does not exacerbate muscular dystrophy in β-sarcoglycan-deficient and laminin α2 chain-deficient mice.
Muscular dystrophy is a group of genetic disorders that lead to muscle wasting and loss of muscle function. Identifying genetic modifiers that alleviate symptoms or enhance the severity of a primary disease helps to understand mechanisms behind disease pathology and facilitates discovery of molecular targets for therapy. Several muscular dystrophies are caused by genetic defects in the components of the dystrophin-glycoprotein adhesion complex (DGC). Thrombospondin-4 overexpression has been shown to mitigate dystrophic disease in mouse models for Duchenne muscular dystrophy (dystrophin deficiency) and limb-girdle muscular dystrophy type 2F (LGMD2F, δ-sarcoglycan deficiency), while deletion of the thrombospondin-4 gene exacerbated the diseases. Hence, thrombospondin-4 has been considered a candidate molecule for therapy of muscular dystrophies involving the DGC. We have investigated whether thrombospondin-4 could act as a genetic modifier for other DGC-associated diseases: limb-girdle muscular dystrophy type 2E (LGMD2E, β-sarcoglycan deficiency) and laminin α2 chain-deficient muscular dystrophy (LAMA2-RD). Deletion of the thrombospondin-4 gene in mouse models for LGMD2E and LAMA2-RD, respectively, did not result in worsening of the dystrophic phenotype. Loss of thrombospondin-4 did not enhance sarcolemma damage and did not impair trafficking of transmembrane receptors integrin α7β1 and dystroglycan in double knockout muscles. Our results suggest that thrombospondin-4 might not be a relevant therapeutic target for all muscular dystrophies involving the DGC. This data also demonstrates that molecular pathology between very similar diseases like LGMD2E and 2F can differ significantly.
2024-01-03 | The MuSK-BMP pathway maintains myofiber size in slow muscle through regulation of Akt-mTOR signaling
Abstract Myofiber size regulation is critical in health, disease, and aging. MuSK (muscle-specific kinase) is a BMP (bone morphogenetic protein) co-receptor that promotes and shapes BMP signaling. MuSK is expressed at all neuromuscular junctions and is also present extrasynaptically in the mouse soleus, whose predominantly oxidative fiber composition is akin to that of human muscle. To investigate the role of the MuSK-BMP pathway in vivo, we generated mice lacking the BMP-binding MuSK Ig3 domain. These ∆Ig3-MuSK mice are viable and fertile with innervation levels comparable to wild type. In 3-month-old mice, myofibers are smaller in the slow soleus, but not in the fast tibialis anterior (TA). Transcriptomic analysis revealed soleus-selective decreases in RNA metabolism and protein synthesis pathways as well as dysregulation of IGF1-Akt-mTOR pathway components. Biochemical analysis showed that Akt-mTOR signaling is reduced in soleus but not TA. We propose that the MuSK-BMP pathway acts extrasynaptically to maintain myofiber size in slow muscle by promoting protein synthetic pathways including IGF1-Akt-mTOR signaling. These results reveal a novel mechanism for regulating myofiber size in slow muscle and introduce the MuSK-BMP pathway as a target for promoting muscle growth and combatting atrophy.
2015-10-12 | Reengineering a transmembrane protein to treat muscular dystrophy using exon skipping
Exon skipping uses antisense oligonucleotides as a treatment for genetic diseases. The antisense oligonucleotides used for exon skipping are designed to bypass premature stop codons in the target RNA and restore reading frame disruption. Exon skipping is currently being tested in humans with dystrophin gene mutations who have Duchenne muscular dystrophy. For Duchenne muscular dystrophy, the rationale for exon skipping derived from observations in patients with naturally occurring dystrophin gene mutations that generated internally deleted but partially functional dystrophin proteins. We have now expanded the potential for exon skipping by testing whether an internal, in-frame truncation of a transmembrane protein γ-sarcoglycan is functional. We generated an internally truncated γ-sarcoglycan protein that we have termed Mini-Gamma by deleting a large portion of the extracellular domain. Mini-Gamma provided functional and pathological benefits to correct the loss of γ-sarcoglycan in a Drosophila model, in heterologous cell expression studies, and in transgenic mice lacking γ-sarcoglycan. We generated a cellular model of human muscle disease and showed that multiple exon skipping could be induced in RNA that encodes a mutant human γ-sarcoglycan. Since Mini-Gamma represents removal of 4 of the 7 coding exons in γ-sarcoglycan, this approach provides a viable strategy to treat the majority of patients with γ-sarcoglycan gene mutations.
2014-02-20 | Enhanced Ca2+ influx from STIM1–Orai1 induces muscle pathology in mouse models of muscular dystrophy
Muscular dystrophy is a progressive muscle wasting disease that is thought to be initiated by unregulated Ca2+ influx into myofibers leading to their death. Store-operated Ca2+ entry (SOCE) through sarcolemmal Ca2+ selective Orai1 channels in complex with STIM1 in the sarcoplasmic reticulum is one such potential disease mechanism for pathologic Ca2+ entry. Here, we generated a mouse model of STIM1 overexpression in skeletal muscle to determine whether this type of Ca2+ entry could induce muscular dystrophy. Myofibers from muscle-specific STIM1 transgenic mice showed a significant increase in SOCE in skeletal muscle, modeling an observed increase in the same current in dystrophic myofibers. Histological and biochemical analysis of STIM1 transgenic mice showed fulminant muscle disease characterized by myofiber necrosis, swollen mitochondria, infiltration of inflammatory cells, enhanced interstitial fibrosis and elevated serum creatine kinase levels. This dystrophic-like disease in STIM1 transgenic mice was abrogated by crossing in a transgene expressing a dominant-negative Orai1 (dnOrai1) mutant. The dnOrai1 transgene also significantly reduced the severity of muscular dystrophy in both mdx (dystrophin mutant mice) and δ-sarcoglycan-deficient (Sgcd−/−) mouse models of disease. Hence, Ca2+ influx across an unstable sarcolemma due to increased activity of a STIM1–Orai1 complex is a disease determinant in muscular dystrophy, and hence, SOCE represents a potential therapeutic target.
cell therapies
2023-06-30 | The super-healing MRL strain promotes muscle growth in muscular dystrophy through a regenerative extracellular matrix
ABSTRACT Genetic background shifts the severity of muscular dystrophy. In mice, the DBA/2J strain confers a more severe muscular dystrophy phenotype, whereas the Murphy’s Roth Large (MRL) strain has “super-healing” properties that reduce fibrosis. A comparative analysis of the Sgcg null model of Limb Girdle Muscular Dystrophy in the DBA/2J versus MRL strain showed the MRL background was associated with greater myofiber regeneration and reduced structural degradation of muscle. Transcriptomic profiling of dystrophic muscle in the DBA/2J and MRL strains indicated strain-dependent expression of the extracellular matrix (ECM) and TGF-β signaling genes. To investigate the MRL ECM, cellular components were removed from dystrophic muscle sections to generate decellularized “myoscaffolds”. Decellularized myoscaffolds from dystrophic mice in the protective MRL strain had significantly less deposition of collagen and matrix-bound TGF-β1 and TGF-β3 throughout the matrix, and dystrophic myoscaffolds from the MRL background were enriched in myokines. C2C12 myoblasts were seeded onto decellularized matrices from Sgcg −/− MRL and Sgcg −/− DBA/2J matrices. Acellular myoscaffolds from the dystrophic MRL background induced myoblast differentiation and growth compared to dystrophic myoscaffolds from the DBA/2J matrices. These studies establish that the MRL background also generates its effect through a highly regenerative ECM, which is active even in muscular dystrophy. Brief Summary The extracellular matrix of the super-healing MRL mouse strain harbors regenerative myokines that improve skeletal muscle growth and function in muscular dystrophy. Graphical Abstract
2019-08-28 | Pluripotent Stem Cell-Based Therapeutics for Muscular Dystrophies
Several methodologies have been reported for the derivation of myogenic progenitors from human pluripotent stem cells. Proof-of-concept studies have shown the therapeutic potential of pluripotent-derived myogenic progenitors in mouse models of MD. Induced pluripotent stem cell technology allows for the generation of MD patient-specific pluripotent stem cells. Progress in genome editing techniques has enabled gene correction of mutations in MD patient-specific induced pluripotent stem cells allowing for their potential therapeutic application in autologous cell transplantation settings. Pluripotent stem cells (PSCs) represent an attractive cell source for treating muscular dystrophies (MDs) since they easily allow for the generation of large numbers of highly regenerative myogenic progenitors. Using reprogramming technology, patient-specific PSCs have been derived for several types of MDs, and genome editing has allowed correction of mutations, opening the opportunity for their therapeutic application in an autologous transplantation setting. However, there has been limited progress on preclinical studies that validate the therapeutic potential of these gene corrected PSC-derived myogenic progenitors. In this review, we highlight the major research advances, challenges, and future prospects towards the development of PSC-based therapeutics for MDs. Pluripotent stem cells (PSCs) represent an attractive cell source for treating muscular dystrophies (MDs) since they easily allow for the generation of large numbers of highly regenerative myogenic progenitors. Using reprogramming technology, patient-specific PSCs have been derived for several types of MDs, and genome editing has allowed correction of mutations, opening the opportunity for their therapeutic application in an autologous transplantation setting. However, there has been limited progress on preclinical studies that validate the therapeutic potential of these gene corrected PSC-derived myogenic progenitors. In this review, we highlight the major research advances, challenges, and future prospects towards the development of PSC-based therapeutics for MDs. use of cells from a healthy donor for cell therapy usually from an individual genetically nonidentical to the patient. use of the patient’s own cells for transplantation. transfer of live cells into a patient for the purpose of mitigating or curing a disease. ability of transplanted cells to reside and function as part of the host environment. If the transplanted cells become part of the muscle fiber and seed the satellite cell pool, it is denoted by the terms myofiber and satellite cell engraftment, respectively. technique of altering a genetic mutation, either by exactly reversing it or by introducing a sequence that will result in equivalent-to-normal function, in order to cure the disease in the patient-derived cells. technique used to modify the genome of the cells in order to fix or create a genetic defect. also known as pericytes, reside in association with blood vessels and are multipotent cells that can give rise to different mesodermal cell types. proliferating muscle progenitors that derive from activated muscle stem cells and give rise to multinucleated myotubes in vitro and muscle fibers in vivo. precursor cells which can differentiate to form muscle in vitro and in vivo. undifferentiated cells that have the potential to differentiate into any cell type of the body. adult muscle stem cells whose nomenclature is based on their location beneath the basal lamina of the muscle fiber. Satellite cells regenerate muscle in response to injury or disease. exogenous DNA sequence introduced into the genome generally for the purpose of expressing a protein of interest.
2019-03-05 | Growth Factor Screening in Dystrophic Muscles Reveals PDGFB/PDGFRB-Mediated Migration of Interstitial Stem Cells
Progressive muscle degeneration followed by dilated cardiomyopathy is a hallmark of muscular dystrophy. Stem cell therapy is suggested to replace diseased myofibers by healthy myofibers, although so far, we are faced by low efficiencies of migration and engraftment of stem cells. Chemokines are signalling proteins guiding cell migration and have been shown to tightly regulate muscle tissue repair. We sought to determine which chemokines are expressed in dystrophic muscles undergoing tissue remodelling. Therefore, we analysed the expression of chemokines and chemokine receptors in skeletal and cardiac muscles from Sarcoglycan-α null, Sarcoglycan-β null and immunodeficient Sgcβ-null mice. We found that several chemokines are dysregulated in dystrophic muscles. We further show that one of these, platelet-derived growth factor-B, promotes interstitial stem cell migration. This finding provides perspective to an approachable mechanism for improving stem cell homing towards dystrophic muscles.
2017-03-17 | Emerging therapeutic strategies for sarcoglycanopathy
Introduction: Sarcoglycanopathy is the name shared by four rare autosomal recessive muscular dystrophies (LGMD2 C-F) that are usually characterized by early onset and rapid progression and an accompanying loss of independent walking since adolescence. Respiratory problems are frequent, and dilated cardiomyopathy may occur, although milder forms have also been described. However, sarcoglycanopathy is currently incurable, and we herein aim to describe the state of the art in the field of treatments for this disease.Areas covered: We summarize the pathogenesis of sarcoglycanopathy, with particular emphasis on the molecular mechanism(s) underlying the disease. We describe the very few published cases of symptomatic treatment with steroids and the gene therapy approaches that have entered phase I/II clinical trials. We then present emerging novel therapeutic strategies explored at the preclinical stage that are expected to replace the defective gene (cell therapy), address general effects of the disease, or address the primary events of the pathogenic mechanism (small molecule-based therapy).Expert opinion: Anti-inflammatory strategies, which are at present empirically applied, warrant further exploration. Although promising and currently being evaluated in clinical trials, gene therapy remains associated with concerns and requires additional confirmation. Thus, novel strategies targeting different aspects of the disease pathogenic mechanism are highly anticipated.
2013-12-01 | A Special Population of Regulatory T Cells Potentiates Muscle Repair
Long recognized to be potent suppressors of immune responses, Foxp3+CD4+ regulatory T (Treg) cells are being rediscovered as regulators of nonimmunological processes. We describe a phenotypically and functionally distinct population of Treg cells that rapidly accumulated in the acutely injured skeletal muscle of mice, just as invading myeloid-lineage cells switched from a proinflammatory to a proregenerative state. A Treg population of similar phenotype accumulated in muscles of genetically dystrophic mice. Punctual depletion of Treg cells during the repair process prolonged the proinflammatory infiltrate and impaired muscle repair, while treatments that increased or decreased Treg activities diminished or enhanced (respectively) muscle damage in a dystrophy model. Muscle Treg cells expressed the growth factor Amphiregulin, which acted directly on muscle satellite cells in vitro and improved muscle repair in vivo. Thus, Treg cells and their products may provide new therapeutic opportunities for wound repair and muscular dystrophies.
gene therapies
2025-03-25 | Sarcoglycanopathies: From clinical diagnosis to new promising therapies
The sarcoglycanopathies are a severe form of limb girdle muscular dystrophy caused by mutations in the sarcoglycan genes SGCA, SGCB, SGCG, and SGCD, leading to reduced or absent expression of the alpha-, beta-, gamma-, and delta-sarcoglycan proteins respectively. Most patients develop a severe disease starting in the first decade of life that progresses quickly and eventually leads to a loss of ambulation before the age of 20. However, there is a marked heterogeneity in the prognosis, and several patients develop a milder phenotype. The factors correlating with disease progression are not completely known, but recent data suggest that remaining protein expression can be a key factor. The diagnosis is confirmed by genetic studies, which are sometimes not confirmative in the case of identifying variants of unknown significance or just one variant. New tools to understand the potential pathogenesis of missense variants have been developed; these are helping in the diagnosis of these diseases. Additionally, recent data on muscle MRI have revealed a characteristic pattern of involvement that can also support the diagnosis of the disease. In recent years, data coming from international collaborative studies have allowed an understanding of disease progression; however, this is only through retrospective data. There are no prospective studies collecting longitudinal data on skeletal and respiratory muscle function or cardiac structure and function progression over time which is hampering the development of new drugs in the field. Clinical trials with gene therapy are underway or are being designed in some of the subtypes of sarcoglycanopathies to advance therapeutic management.
2024-05-06 | Advanced therapeutic approaches in sarcoglycanopathies
Sarcoglycanopathies are rare autosomal recessive diseases belonging to the family of limb-girdle muscular dystrophies. They are caused by mutations in the genes coding for α-, β-, γ-, and δ-sarcoglycan. The mutations impair the assembly of a key structural complex, which normally protects the sarcolemma of striated muscle from contraction-derived stress. Although heterogeneous, sarcoglycanopathies are characterized by progressive muscle degeneration, increased serum creatine kinase levels, loss of ambulation often during adolescence, and variable cardio-respiratory impairment. Genetic defects can impair sarcoglycan synthesis or produce a protein that is defective in folding. There is currently no effective treatment available; however, both gene replacement strategy and small molecule-based approaches show great promise and have entered or are starting to enter clinical trials.
2021-07-28 | Sarcoglycanopathies: an update
Sarcoglycanopathies are the most severe forms of autosomal recessive limb-girdle muscular dystrophies (LGMDs), constituting about 10-25% of LGMDs. The clinical phenotype is variable, but onset is usually in the first decade of life. Patients present muscle hypertrophy, elevated CK, variable muscle weaknesses, and progressive loss of ambulation. Four subtypes are known: LGMDR3, LGMDR4, LGMDR5 and LGMDR6, caused, respectively, by mutations in the SGCA, SGCB,SGCG and SGCD genes. Their four coded proteins, α-SG, ß-SG, λ-SG and δ-SG are part of the dystrophin-glycoprotein complex (DGC) present in muscle sarcolemma, which acts as a linker between the cytoskeleton of the muscle fiber and the extracellular matrix, providing mechanical support to the sarcolemma during myofiber contraction. Many different mutations have already been identified in all the sarcoglycan genes, with a predominance of some mutations in different populations. The diagnosis is currently based on the molecular screening for these mutations. Therapeutic approaches include the strategy of gene replacement mediated by a vector derived from adeno-associated virus (AAV). Pre-clinical studies have shown detectable levels of SG proteins in the muscle, and some improvement in the phenotype, in animal models. Therapeutic trials in humans are ongoing.
2019-05-10 | An AAV-SGCG Dose-Response Study in a γ-Sarcoglycanopathy Mouse Model in the Context of Mechanical Stress
Sarcoglycanopathies are rare autosomic limb girdle muscular dystrophies caused by mutations in one of the genes coding for sarcoglycans. Sarcoglycans form a complex, which is an important part of the dystrophin-associated glycoprotein complex and which protects the sarcolemma against muscle contraction-induced damage. Absence of one of the sarcoglycans on the plasma membrane reduces the stability of the whole complex and perturbs muscle fiber membrane integrity. There is currently no curative treatment for any of the sarcoglycanopathies. A first clinical trial to evaluate the safety of a recombinant AAV2/1 vector expressing γ-sarcoglycan using an intramuscular route of administration showed limited expression of the transgene and good tolerance of the approach. In this report, we undertook a dose-effect study in mice to evaluate the efficiency of an AAV2/8-expressing γ-sarcoglycan controlled by a muscle-specific promoter with a systemic mode of administration. We observed a dose-related efficiency with a nearly complete restoration of gamma sarcoglycan (SGCG) expression, histological appearance, biomarker level, and whole-body strength at the highest dose tested. In addition, our data suggest that a high expression threshold level must be achieved for effective protection of the transduced muscle, while a suboptimal transgene expression level might be less protective in the context of mechanical stress. Sarcoglycanopathies are rare autosomic limb girdle muscular dystrophies caused by mutations in one of the genes coding for sarcoglycans. Sarcoglycans form a complex, which is an important part of the dystrophin-associated glycoprotein complex and which protects the sarcolemma against muscle contraction-induced damage. Absence of one of the sarcoglycans on the plasma membrane reduces the stability of the whole complex and perturbs muscle fiber membrane integrity. There is currently no curative treatment for any of the sarcoglycanopathies. A first clinical trial to evaluate the safety of a recombinant AAV2/1 vector expressing γ-sarcoglycan using an intramuscular route of administration showed limited expression of the transgene and good tolerance of the approach. In this report, we undertook a dose-effect study in mice to evaluate the efficiency of an AAV2/8-expressing γ-sarcoglycan controlled by a muscle-specific promoter with a systemic mode of administration. We observed a dose-related efficiency with a nearly complete restoration of gamma sarcoglycan (SGCG) expression, histological appearance, biomarker level, and whole-body strength at the highest dose tested. In addition, our data suggest that a high expression threshold level must be achieved for effective protection of the transduced muscle, while a suboptimal transgene expression level might be less protective in the context of mechanical stress.
2019-03-01 | Various effects of AAV9-mediated βARKct gene therapy on the heart in dystrophin-deficient (mdx) mice and δ-sarcoglycan-deficient (Sgcd-/-) mice
So far effective strategies to treat cardiomyopathy in patients with muscular dystrophies are still not clearly defined. Previously, treatment with β-blockers showed beneficial effects on the development of cardiomyopathy in dystrophin-deficient (mdx) mice, but not in δ-sarcoglycan-deficient (Sgcd-/-) mice. We therefore aimed to study a more specific approach to target maladaptive β-adrenergic signalling in these mice. It has been shown that lowering cardiac G-protein-coupled-receptor-kinase-2 (GRK2) activity with βARKct expression, a peptide inhibitor of protein-coupled-receptor-kinase-2 (GRK2), results in improvement of heart failure in several different animal models. We therefore investigated whether adeno-associated virus type 9 (AAV9)-mediated gene delivery of βARKct, could ameliorate cardiac pathology in mdx and Sgcd-/- mice. We found that long-term treatment with AAV9- βARKct-cDNA with a cardiac-specific promoter significantly improves left ventricular systolic function and reduces myocardial hypertrophy in mdx mice, whereas only mild beneficial effects on cardiac function is observed in Sgcd-/- mice. Interestingly, in contrast to mdx mice neither GRK2 nor nuclear-factor-kappaB (NFκB) were upregulated in Sgcd-/- mice. Taken together, effectiveness of AAV-mediated βARKct therapy may vary between different genetic mutations and presumably depend on the state of adrenergic dysregulation mediated through the upregulation of GRK2.
small molecules
2026-05-19 | The flavanol (-)-epicatechin induced different histological features and myogenic protein levels in triceps, gastrocnemius and plantaris of δ-sarcoglycan-deficient mice.
Limb-girdle muscular dystrophies (LGMD) exhibit a wide range of disease severity, affecting various parts of the skeletal muscle to varying degrees. This may be associated with differences in the degeneration and regeneration processes in different muscles. We previously reported that muscles with different metabolic characteristics showed distinct levels of proteins involved in the muscle regeneration process in δ-sarcoglycan-deficient mice, a model for LGMDR6. These phenomena may be relevant to test potential therapeutic compounds in myopathies. In this study, we analyzed the effect of (-)-epicatechin (Epi), a flavanol enriched in cacao that has shown beneficial effects in skeletal muscle, in different muscles of the δ-sarcoglycan-deficient mice. Histochemical analysis showed that dystrophic triceps and gastrocnemius had a higher level of fibrosis than plantaris, and Epi reduced this. In addition, Epi increased the cross-sectional area of dystrophic triceps fibers, which was associated with a higher fusion index. In contrast, Epi reduced the index fusion in dystrophic plantaris. Western blot analysis demonstrates that Epi increases protein levels of Pax7, β-catenin, and myogenin in the dystrophic triceps and increases protein levels of β-catenin and myogenin in the gastrocnemius. In contrast, in the plantaris, none of the protein levels was modified. All these results suggest that muscles with different metabolic characteristics and physiological demands could respond differentially to pharmacological therapies in dystrophic muscles.
2026-05-06 | (-)-Epicatechin modulates skeletal muscle inflammatory response in a mouse model of Limb-Girdle Muscular Dystrophy 2F
Abstract Skeletal muscle possesses remarkable regenerative capacity. However, in limb-girdle muscular dystrophy-2F (LGMD2F), this capacity is compromised by persistent innate immune activation, whose transcriptional landscape remains unexplored. In parallel, (-)-Epicatechin has emerged as a promising compound with beneficial effects on muscle and notable anti-inflammatory properties. We therefore used (-)-Epicatechin treatment to test whether it can alleviate LGMD2F-associated transcriptional and immune dysregulation. Here we provide the first transcriptomic characterization of LGMD2F using the Sgcd ⁻/⁻ mouse model, along with the first RNA-sequencing-based evaluation of (-)-Epicatechin treatment. We profiled two functionally distinct muscles — the soleus and EDL — through bulk RNA-sequencing coupled with immune cell-deconvolution. Sgcd ⁻/⁻ muscles exhibited marked transcriptional dysregulation, more pronounced in the soleus and associated with enhanced innate immune signaling. (-)-Epicatechin induced a muscle- and genotype-dependent transcriptional response: in wild-type animals, the EDL displayed the highest number of differentially expressed transcripts, whereas in Sgcd ⁻/⁻ mice, the soleus showed the most prominent response. This shift was accompanied by downregulation of Toll-like receptor and RIG-I-like receptor pathways, along with suppression of NF-κB2 and interferon-stimulated genes. Together, these findings identify innate immune overactivation as a central feature of LGMD2F and reveal (-)-Epicatechin as a context-dependent modulator of muscle-specific transcriptional responses.
2025-03-07 | Dysregulated ATX-LPA and YAP/TAZ signaling in dystrophic Sgcd-/- mice with early fibrosis and inflammation.
Sarcoglycanopathies are muscle dystrophies caused by mutations in the genes encoding sarcoglycans (α, β, γ, and δ) that can destabilize the dystrophin-associated glycoprotein complex at the sarcolemma, leaving muscle fibers vulnerable to damage after contraction, followed by inflammatory and fibrotic responses and resulting in muscle weakness and atrophy. Two signaling pathways have been implicated in fibrosis and inflammation in various tissues: autotaxin/lysophosphatidic acid (ATX-LPA) and yes-associated protein 1/transcriptional co-activator with PDZ-binding motif (YAP/TAZ). LPA, synthesized by ATX, can act as a pleiotropic molecule due to its multiple receptors. Two Hippo pathway effectors, YAP/TAZ, can be dephosphorylated by LPA and translocated to the nucleus. They induce several target genes, such as CCN2/CTGF, involved in fibrosis and inflammation. However, no detailed characterization of these processes or whether these pathways change early in the development of sarcoglycanopathy has been evaluated in skeletal muscle. Using the δ-sarcoglycan knockout mouse model (Sgcd-/-), we investigated components of these pathways, inflammatory and fibrotic markers, and contractile properties of different skeletal muscles (triceps-TR, gastrocnemius-GST, diaphragm-DFG, tibialis anterior-TA, and extensor digitorum longus-EDL) at one and two months of age. We found that Sgcd-/- mice show early dystrophic features (fiber damage/necrosis, centrally nucleated fibers, inflammatory infiltrate, and regenerated fibers) followed by later fiber size reduction in TR, GST, and DFG. These changes are concomitant with an early inflammatory and fibrotic response in these muscles. Sgcd-/- mice also have early impaired force generation in the TA and EDL, and resistance to mechanical damage in the EDL. In addition, an early dysregulation of the ATX-LPA axis and the YAP/TAZ signaling pathway in the TR, GST, and DFG was observed in these mice. The ATX-LPA axis and the YAP/TAZ signaling pathway, which are involved in inflammation and fibrosis, are dysregulated in skeletal muscle from an early age in Sgcd-/- mice. These changes are concomitant with a fibrotic and inflammatory response in these mice. Unraveling the role of the LPA axis and YAP/TAZ in sarcoglycanopathy holds great promise for improving our understanding of disease pathogenesis and identifying novel therapeutic targets for this currently incurable group of muscle disorders.
2023-05-29 | The Role of P2X7 Purinoceptors in the Pathogenesis and Treatment of Muscular Dystrophies
Muscular dystrophies are inherited neuromuscular diseases, resulting in progressive disability and often affecting life expectancy. The most severe, common types are Duchenne muscular dystrophy (DMD) and Limb-girdle sarcoglycanopathy, which cause advancing muscle weakness and wasting. These diseases share a common pathomechanism where, due to the loss of the anchoring dystrophin (DMD, dystrophinopathy) or due to mutations in sarcoglycan-encoding genes (LGMDR3 to LGMDR6), the α-sarcoglycan ecto-ATPase activity is lost. This disturbs important purinergic signaling: An acute muscle injury causes the release of large quantities of ATP, which acts as a damage-associated molecular pattern (DAMP). DAMPs trigger inflammation that clears dead tissues and initiates regeneration that eventually restores normal muscle function. However, in DMD and LGMD, the loss of ecto-ATPase activity, that normally curtails this extracellular ATP (eATP)-evoked stimulation, causes exceedingly high eATP levels. Thus, in dystrophic muscles, the acute inflammation becomes chronic and damaging. The very high eATP over-activates P2X7 purinoceptors, not only maintaining the inflammation but also tuning the potentially compensatory P2X7 up-regulation in dystrophic muscle cells into a cell-damaging mechanism exacerbating the pathology. Thus, the P2X7 receptor in dystrophic muscles is a specific therapeutic target. Accordingly, the P2X7 blockade alleviated dystrophic damage in mouse models of dystrophinopathy and sarcoglycanopathy. Therefore, the existing P2X7 blockers should be considered for the treatment of these highly debilitating diseases. This review aims to present the current understanding of the eATP-P2X7 purinoceptor axis in the pathogenesis and treatment of muscular dystrophies.
2019-06-26 | SIRT1 deficiency interferes with membrane resealing after cell membrane injury
Activation of SIRT1, an NAD+-dependent protein deacetylase, ameliorates muscular pathophysiology of δ-sarcoglycan-deficient TO-2 hamsters and dystrophin-deficient mdx mice. We found that SIRT1 was highly expressed beneath the cellular membranes of muscle cells. To elucidate functional roles of SIRT1 on muscles, skeletal muscle-specific SIRT1 knockout mice (SIRT1-MKO) were generated. SIRT1-MKO mice showed muscular pathology similar to mild muscular dystrophies with increased numbers of centrally nucleated small myofibers and decreased numbers of middle-sized (2000–3001 μm2) myofibers compared to those of wild-type (WT) mice. Accordingly, SIRT1-MKO mice showed significantly decreased exercise capacity in treadmill and inverted hanging tests with higher levels of serum creatine kinase activities compared with those in WT mice. Evans blue dye uptake after exercise was greater in the muscles of SIRT1-MKO than those of WT mice, suggesting membrane fragility in SIRT1-MKO mice. Because SIRT1 was dominantly localized beneath the membranes of muscular cells, SIRT1 may have a new role in the membranes. We found that levels of fluorescent FM1-43 dye intake after laser-induced membrane disruption in C2C12 cells were significantly increased by SIRT1 inhibitors or Sirt1-siRNA compared with those of control cells. Inhibition of SIRT1 or SIRT1-knockdown severely disturbed the dynamic aggregation of membrane vesicles under the injured site but did not affect expression levels of membrane repair proteins. These data suggested that SIRT1 had a critical role in the resealing of membrane-ruptured muscle cells, which could affect phenotypes of SIRT1-MKO mice. To our knowledge, this report is the first to demonstrate that SIRT1 affected plasma-membrane repair mechanisms.
proteins
2025-01-22 | Sarcoglycans are enriched at the neuromuscular junction in a nerve-dependent manner
Abstract Sarcoglycanopathies are heterogeneous proximo-distal diseases presenting severe muscle alterations. Although there are 6 different sarcoglycan isoforms, sarcoglycanopathies are caused exclusively by mutations in genes coding for one of the four sarcoglycan transmembrane proteins (alpha, beta, gamma and delta) forming the sarcoglycan complex (SGC) in skeletal and cardiac muscle. Little is known about the different roles of the SGC beyond the dystrophin glycoprotein complex (DGC) structural role. Here, we show that SGC proteins are enriched at the post-synaptic membrane of neuromuscular junctions (NMJs). Using a mouse model lacking the beta-sarcoglycan subunit, we describe for the first time that the loss of the SGC in the NMJ area results in alterations of pre- and postsynaptic membrane, as well as a significant reduction of membrane potential. Moreover, using different denervated wild-type mouse models, we demonstrate that nerve presence precedes the sarcoglycan enrichment at NMJ, suggesting a nerve-dependent sarcoglycan expression. Altogether, our findings suggest that pathological decline should no longer be understood only in terms of sarcolemma damage but also in terms of sarcoglycans’ participation in the NMJ. Henceforth, our work paves the way for the identification of new mechanisms involving sarcoglycans and new approaches for the treatment of sarcoglycanopathies.
2024-06-27 | Thrombospondin-4 deletion does not exacerbate muscular dystrophy in β-sarcoglycan-deficient and laminin α2 chain-deficient mice.
Muscular dystrophy is a group of genetic disorders that lead to muscle wasting and loss of muscle function. Identifying genetic modifiers that alleviate symptoms or enhance the severity of a primary disease helps to understand mechanisms behind disease pathology and facilitates discovery of molecular targets for therapy. Several muscular dystrophies are caused by genetic defects in the components of the dystrophin-glycoprotein adhesion complex (DGC). Thrombospondin-4 overexpression has been shown to mitigate dystrophic disease in mouse models for Duchenne muscular dystrophy (dystrophin deficiency) and limb-girdle muscular dystrophy type 2F (LGMD2F, δ-sarcoglycan deficiency), while deletion of the thrombospondin-4 gene exacerbated the diseases. Hence, thrombospondin-4 has been considered a candidate molecule for therapy of muscular dystrophies involving the DGC. We have investigated whether thrombospondin-4 could act as a genetic modifier for other DGC-associated diseases: limb-girdle muscular dystrophy type 2E (LGMD2E, β-sarcoglycan deficiency) and laminin α2 chain-deficient muscular dystrophy (LAMA2-RD). Deletion of the thrombospondin-4 gene in mouse models for LGMD2E and LAMA2-RD, respectively, did not result in worsening of the dystrophic phenotype. Loss of thrombospondin-4 did not enhance sarcolemma damage and did not impair trafficking of transmembrane receptors integrin α7β1 and dystroglycan in double knockout muscles. Our results suggest that thrombospondin-4 might not be a relevant therapeutic target for all muscular dystrophies involving the DGC. This data also demonstrates that molecular pathology between very similar diseases like LGMD2E and 2F can differ significantly.
2024-01-03 | The MuSK-BMP pathway maintains myofiber size in slow muscle through regulation of Akt-mTOR signaling
Abstract Myofiber size regulation is critical in health, disease, and aging. MuSK (muscle-specific kinase) is a BMP (bone morphogenetic protein) co-receptor that promotes and shapes BMP signaling. MuSK is expressed at all neuromuscular junctions and is also present extrasynaptically in the mouse soleus, whose predominantly oxidative fiber composition is akin to that of human muscle. To investigate the role of the MuSK-BMP pathway in vivo, we generated mice lacking the BMP-binding MuSK Ig3 domain. These ∆Ig3-MuSK mice are viable and fertile with innervation levels comparable to wild type. In 3-month-old mice, myofibers are smaller in the slow soleus, but not in the fast tibialis anterior (TA). Transcriptomic analysis revealed soleus-selective decreases in RNA metabolism and protein synthesis pathways as well as dysregulation of IGF1-Akt-mTOR pathway components. Biochemical analysis showed that Akt-mTOR signaling is reduced in soleus but not TA. We propose that the MuSK-BMP pathway acts extrasynaptically to maintain myofiber size in slow muscle by promoting protein synthetic pathways including IGF1-Akt-mTOR signaling. These results reveal a novel mechanism for regulating myofiber size in slow muscle and introduce the MuSK-BMP pathway as a target for promoting muscle growth and combatting atrophy.
2015-10-12 | Reengineering a transmembrane protein to treat muscular dystrophy using exon skipping
Exon skipping uses antisense oligonucleotides as a treatment for genetic diseases. The antisense oligonucleotides used for exon skipping are designed to bypass premature stop codons in the target RNA and restore reading frame disruption. Exon skipping is currently being tested in humans with dystrophin gene mutations who have Duchenne muscular dystrophy. For Duchenne muscular dystrophy, the rationale for exon skipping derived from observations in patients with naturally occurring dystrophin gene mutations that generated internally deleted but partially functional dystrophin proteins. We have now expanded the potential for exon skipping by testing whether an internal, in-frame truncation of a transmembrane protein γ-sarcoglycan is functional. We generated an internally truncated γ-sarcoglycan protein that we have termed Mini-Gamma by deleting a large portion of the extracellular domain. Mini-Gamma provided functional and pathological benefits to correct the loss of γ-sarcoglycan in a Drosophila model, in heterologous cell expression studies, and in transgenic mice lacking γ-sarcoglycan. We generated a cellular model of human muscle disease and showed that multiple exon skipping could be induced in RNA that encodes a mutant human γ-sarcoglycan. Since Mini-Gamma represents removal of 4 of the 7 coding exons in γ-sarcoglycan, this approach provides a viable strategy to treat the majority of patients with γ-sarcoglycan gene mutations.
2014-02-20 | Enhanced Ca2+ influx from STIM1–Orai1 induces muscle pathology in mouse models of muscular dystrophy
Muscular dystrophy is a progressive muscle wasting disease that is thought to be initiated by unregulated Ca2+ influx into myofibers leading to their death. Store-operated Ca2+ entry (SOCE) through sarcolemmal Ca2+ selective Orai1 channels in complex with STIM1 in the sarcoplasmic reticulum is one such potential disease mechanism for pathologic Ca2+ entry. Here, we generated a mouse model of STIM1 overexpression in skeletal muscle to determine whether this type of Ca2+ entry could induce muscular dystrophy. Myofibers from muscle-specific STIM1 transgenic mice showed a significant increase in SOCE in skeletal muscle, modeling an observed increase in the same current in dystrophic myofibers. Histological and biochemical analysis of STIM1 transgenic mice showed fulminant muscle disease characterized by myofiber necrosis, swollen mitochondria, infiltration of inflammatory cells, enhanced interstitial fibrosis and elevated serum creatine kinase levels. This dystrophic-like disease in STIM1 transgenic mice was abrogated by crossing in a transgene expressing a dominant-negative Orai1 (dnOrai1) mutant. The dnOrai1 transgene also significantly reduced the severity of muscular dystrophy in both mdx (dystrophin mutant mice) and δ-sarcoglycan-deficient (Sgcd−/−) mouse models of disease. Hence, Ca2+ influx across an unstable sarcolemma due to increased activity of a STIM1–Orai1 complex is a disease determinant in muscular dystrophy, and hence, SOCE represents a potential therapeutic target.
cell therapies
2023-06-30 | The super-healing MRL strain promotes muscle growth in muscular dystrophy through a regenerative extracellular matrix
ABSTRACT Genetic background shifts the severity of muscular dystrophy. In mice, the DBA/2J strain confers a more severe muscular dystrophy phenotype, whereas the Murphy’s Roth Large (MRL) strain has “super-healing” properties that reduce fibrosis. A comparative analysis of the Sgcg null model of Limb Girdle Muscular Dystrophy in the DBA/2J versus MRL strain showed the MRL background was associated with greater myofiber regeneration and reduced structural degradation of muscle. Transcriptomic profiling of dystrophic muscle in the DBA/2J and MRL strains indicated strain-dependent expression of the extracellular matrix (ECM) and TGF-β signaling genes. To investigate the MRL ECM, cellular components were removed from dystrophic muscle sections to generate decellularized “myoscaffolds”. Decellularized myoscaffolds from dystrophic mice in the protective MRL strain had significantly less deposition of collagen and matrix-bound TGF-β1 and TGF-β3 throughout the matrix, and dystrophic myoscaffolds from the MRL background were enriched in myokines. C2C12 myoblasts were seeded onto decellularized matrices from Sgcg −/− MRL and Sgcg −/− DBA/2J matrices. Acellular myoscaffolds from the dystrophic MRL background induced myoblast differentiation and growth compared to dystrophic myoscaffolds from the DBA/2J matrices. These studies establish that the MRL background also generates its effect through a highly regenerative ECM, which is active even in muscular dystrophy. Brief Summary The extracellular matrix of the super-healing MRL mouse strain harbors regenerative myokines that improve skeletal muscle growth and function in muscular dystrophy. Graphical Abstract
2019-08-28 | Pluripotent Stem Cell-Based Therapeutics for Muscular Dystrophies
Several methodologies have been reported for the derivation of myogenic progenitors from human pluripotent stem cells. Proof-of-concept studies have shown the therapeutic potential of pluripotent-derived myogenic progenitors in mouse models of MD. Induced pluripotent stem cell technology allows for the generation of MD patient-specific pluripotent stem cells. Progress in genome editing techniques has enabled gene correction of mutations in MD patient-specific induced pluripotent stem cells allowing for their potential therapeutic application in autologous cell transplantation settings. Pluripotent stem cells (PSCs) represent an attractive cell source for treating muscular dystrophies (MDs) since they easily allow for the generation of large numbers of highly regenerative myogenic progenitors. Using reprogramming technology, patient-specific PSCs have been derived for several types of MDs, and genome editing has allowed correction of mutations, opening the opportunity for their therapeutic application in an autologous transplantation setting. However, there has been limited progress on preclinical studies that validate the therapeutic potential of these gene corrected PSC-derived myogenic progenitors. In this review, we highlight the major research advances, challenges, and future prospects towards the development of PSC-based therapeutics for MDs. Pluripotent stem cells (PSCs) represent an attractive cell source for treating muscular dystrophies (MDs) since they easily allow for the generation of large numbers of highly regenerative myogenic progenitors. Using reprogramming technology, patient-specific PSCs have been derived for several types of MDs, and genome editing has allowed correction of mutations, opening the opportunity for their therapeutic application in an autologous transplantation setting. However, there has been limited progress on preclinical studies that validate the therapeutic potential of these gene corrected PSC-derived myogenic progenitors. In this review, we highlight the major research advances, challenges, and future prospects towards the development of PSC-based therapeutics for MDs. use of cells from a healthy donor for cell therapy usually from an individual genetically nonidentical to the patient. use of the patient’s own cells for transplantation. transfer of live cells into a patient for the purpose of mitigating or curing a disease. ability of transplanted cells to reside and function as part of the host environment. If the transplanted cells become part of the muscle fiber and seed the satellite cell pool, it is denoted by the terms myofiber and satellite cell engraftment, respectively. technique of altering a genetic mutation, either by exactly reversing it or by introducing a sequence that will result in equivalent-to-normal function, in order to cure the disease in the patient-derived cells. technique used to modify the genome of the cells in order to fix or create a genetic defect. also known as pericytes, reside in association with blood vessels and are multipotent cells that can give rise to different mesodermal cell types. proliferating muscle progenitors that derive from activated muscle stem cells and give rise to multinucleated myotubes in vitro and muscle fibers in vivo. precursor cells which can differentiate to form muscle in vitro and in vivo. undifferentiated cells that have the potential to differentiate into any cell type of the body. adult muscle stem cells whose nomenclature is based on their location beneath the basal lamina of the muscle fiber. Satellite cells regenerate muscle in response to injury or disease. exogenous DNA sequence introduced into the genome generally for the purpose of expressing a protein of interest.
2019-03-05 | Growth Factor Screening in Dystrophic Muscles Reveals PDGFB/PDGFRB-Mediated Migration of Interstitial Stem Cells
Progressive muscle degeneration followed by dilated cardiomyopathy is a hallmark of muscular dystrophy. Stem cell therapy is suggested to replace diseased myofibers by healthy myofibers, although so far, we are faced by low efficiencies of migration and engraftment of stem cells. Chemokines are signalling proteins guiding cell migration and have been shown to tightly regulate muscle tissue repair. We sought to determine which chemokines are expressed in dystrophic muscles undergoing tissue remodelling. Therefore, we analysed the expression of chemokines and chemokine receptors in skeletal and cardiac muscles from Sarcoglycan-α null, Sarcoglycan-β null and immunodeficient Sgcβ-null mice. We found that several chemokines are dysregulated in dystrophic muscles. We further show that one of these, platelet-derived growth factor-B, promotes interstitial stem cell migration. This finding provides perspective to an approachable mechanism for improving stem cell homing towards dystrophic muscles.
2017-03-17 | Emerging therapeutic strategies for sarcoglycanopathy
Introduction: Sarcoglycanopathy is the name shared by four rare autosomal recessive muscular dystrophies (LGMD2 C-F) that are usually characterized by early onset and rapid progression and an accompanying loss of independent walking since adolescence. Respiratory problems are frequent, and dilated cardiomyopathy may occur, although milder forms have also been described. However, sarcoglycanopathy is currently incurable, and we herein aim to describe the state of the art in the field of treatments for this disease.Areas covered: We summarize the pathogenesis of sarcoglycanopathy, with particular emphasis on the molecular mechanism(s) underlying the disease. We describe the very few published cases of symptomatic treatment with steroids and the gene therapy approaches that have entered phase I/II clinical trials. We then present emerging novel therapeutic strategies explored at the preclinical stage that are expected to replace the defective gene (cell therapy), address general effects of the disease, or address the primary events of the pathogenic mechanism (small molecule-based therapy).Expert opinion: Anti-inflammatory strategies, which are at present empirically applied, warrant further exploration. Although promising and currently being evaluated in clinical trials, gene therapy remains associated with concerns and requires additional confirmation. Thus, novel strategies targeting different aspects of the disease pathogenic mechanism are highly anticipated.
2013-12-01 | A Special Population of Regulatory T Cells Potentiates Muscle Repair
Long recognized to be potent suppressors of immune responses, Foxp3+CD4+ regulatory T (Treg) cells are being rediscovered as regulators of nonimmunological processes. We describe a phenotypically and functionally distinct population of Treg cells that rapidly accumulated in the acutely injured skeletal muscle of mice, just as invading myeloid-lineage cells switched from a proinflammatory to a proregenerative state. A Treg population of similar phenotype accumulated in muscles of genetically dystrophic mice. Punctual depletion of Treg cells during the repair process prolonged the proinflammatory infiltrate and impaired muscle repair, while treatments that increased or decreased Treg activities diminished or enhanced (respectively) muscle damage in a dystrophy model. Muscle Treg cells expressed the growth factor Amphiregulin, which acted directly on muscle satellite cells in vitro and improved muscle repair in vivo. Thus, Treg cells and their products may provide new therapeutic opportunities for wound repair and muscular dystrophies.
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