2026-07-09 | AAV.hBAG3 Gene Therapy Improves Phenotype in a Valosin Containing Protein Mouse Model of Hereditary Inclusion Body Myositis.
Mutations in the valosin-containing protein (VCP) gene lead to a hereditary type of inclusion body myositis (hIBM), in which sarcoplasmic and myonuclear inclusions with TAR DNA-binding protein 43 (TDP-43) pathology and mitochondrial abnormalities are observed in histological analysis. Pathophysiological conditions in the cell cause the protein quality control system to depend on the autophagy-lysosome pathway (ALP) for degradation of accumulated misfolded proteins and mitochondrial turnover. BCL2-associated athanogene 3 (BAG3) protein has a role in initiating the ALP. Our aim was to ameliorate disease processes resulting from mitochondrial abnormalities and misfolded protein aggregation by upregulating the ALP through overexpression of human BAG3 (hBAG3). The VCP-A232E mouse, a model for hIBM, received AAVrh74.tMCK.hBAG3 systemically at 3 months of age, and outcome measures, including functional, histological, and molecular studies, were assessed 9 months post-gene delivery. hBAG3 treatment improved treadmill running distance and rotarod duration, reduced the number of TDP-43-positive aggregates, and decreased the number of fibers showing abnormalities in mitochondrial enzyme histochemistry, compared with the untreated cohort. Moreover, hBAG3 gene therapy resulted in improvements in mitophagy and mitochondrial homeostasis observed as increased levels in mitophagy markers Parkin and Bnip3, mitochondria biogenesis marker Pgc1α and mitochondrial DNA-encoded subunits of complex IV, Cox1 and Cox3. In addition, the LC-II/I ratio increased, indicating increased autophagic flux. Our study presents evidence that the strategy of supporting the ALP system by overexpressing BAG3 has potential therapeutic use for myodegenerative conditions associated with abnormal protein aggregates and mitochondrial turnover.
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2026-06-20 | Collagen VI is a fibrosis-associated signal disrupting muscle regeneration across distinct human myopathies.
Muscle fibrosis is a major driver of progression in diverse myopathies, yet the conserved molecular mediators of this process in humans remain poorly defined. Here, we identify collagen VI as a common regeneration-impairing extracellular matrix (ECM) component across three distinct human myopathies: Duchenne Muscular Dystrophy (DMD), Oculopharyngeal Muscular Dystrophy (OPMD), and Inclusion Body Myositis (IBM). Proteomic profiling of fibrotic biopsies reveals consistent upregulation of collagen VI and laminin γ1, alongside disease-specific alterations. Fibroadipogenic progenitors (FAPs) are the predominant source of these ECM components, including collagen VI and laminin γ1. Functionally, xenotransplantation of patient-derived FAPs into regenerating mouse muscle induces localized collagen deposition, myofiber atrophy, and depletion of Pax7⁺ muscle stem cells. Mechanistic assays demonstrate that FAP-derived collagen VI is sufficient to impair myogenic fusion, while silencing COL6 in patient FAPs restores fusion capacity, directly linking pathological collagen VI deposition to regeneration failure. Our findings uncover collagen VI as a conserved effector of fibrosis and stem cell niche disruption in human myopathies, positioning it as a potential therapeutic target across genetically and clinically distinct muscle diseases.
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2026-06-02 | Genetic Variation in Follistatin and its Role in Muscle Recovery and Hypertrophy: A Dose-Dependent Mechanistic Review
The Follistatin (FST)--Myostatin axis is a primary regulator of skeletalmuscle plasticity, governing both hypertrophy and regenerative capacity. Whilethe anabolic potential of Follistatin overexpression is well-established, thespecific signaling consequences of graded, physiological perturbations (such asthose arising from natural genetic variation or titrated gene therapies) remainunderexplored. This review synthesizes current literature to distinguish betweenthe effects of binary overexpression versus dose-dependent modulation ofFollistatin. We examine the dual mechanisms of FST action: the canonicalsuppression of Smad2/3 signaling via Myostatin/Activin blockade and thecooperative activation of the Akt/mTOR/S6K pathway through obligate IGF-Ireceptor co-signaling. Emerging evidence from human FST polymorphism studiesdemonstrates that naturally occurring variation in the FST locus tonicallymodulates muscle mass and exercise adaptability across the lifespan. Inparallel, phase 1/2a gene therapy trials show that AAV-mediated FST deliveryproduces measurable functional gains in patients with Becker muscular dystrophyand sporadic inclusion body myositis. The same ligand promiscuity that makesFST potent also renders it hazardous in excess: supraphysiological levelssuppress FSH secretion, impair reproductive function, and, through inadvertentGDF11 inhibition, compromise bone integrity. We conclude that future researchmust map the graded dose--response landscape of FST to define the therapeuticwindow for muscle recovery and hypertrophy while avoiding systemic off-targettoxicity.
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