2026-06-21 | Consistent MYORG and STRADB Downregulation in DMD and LGMD: Rationale for Deoxygalactonojirimycin Repurposing in Dystrophic and Aging Muscle

Abstract Background MYORG (myogenesis-regulating glycosidase) and STRADB (STE20-related kinase adapter protein beta) were previously identified as activity-mediated skeletal muscle genes with potential roles in frailty and sarcopenia. We hypothesized that, if these genes are sustained by neuromuscular contractile activity, their expression should be consistently downregulated in muscular dystrophies, conditions defined by progressive muscle degeneration and secondary functional disuse. Methods We performed a systematic cross-dataset transcriptomic analysis of five publicly available GEO microarray datasets of human skeletal muscle. Discovery analysis was conducted in GSE3307 (Affymetrix HG-U133A/B; samples spanning DMD, LGMD2A/B/I, BMD, FSHD, JDM, ALS, AQM versus healthy controls). Independent external validation was performed in GSE38417 (HG-U133 Plus 2.0, DMD; n=16/6), GSE11681 (HG-U133A/B, LGMD2A; n=8-10/9-10), GSE465 (HG-U95Av2/B/C, multi-disease), and GSE1007 (HG-U95B/C/E, DMD; n=10-11/11). Raw CEL files underwent array-level quality assessment using NUSE and RLE diagnostics prior to normalization. Seven poor-quality arrays were excluded (none from Control, DMD, or LGMD groups). Remaining arrays were processed by robust multi-array average (RMA) normalization, and differential expression was assessed by limma with Benjamini-Hochberg FDR correction. Results MYORG was significantly downregulated in DMD (log2 fold-change [logFC] = -0.93, adj.P<0.001), LGMD2A (logFC = -0.82, adj.P<0.01), LGMD2B (logFC = -1.01, adj.P<0.01), and LGMD2I (logFC = -1.03, adj.P<0.01) in GSE3307. STRADB was significantly reduced in DMD (logFC = -0.33, adj.P<0.05) and showed a near-significant trend in LGMD2I (logFC = - 0.42, adj.P = 0.061). MYORG downregulation in DMD was independently replicated in GSE38417 (logFC = -1.40, adj.P<0.001) and GSE1007 (logFC = -0.80, adj.P<0.001). STRADB was also significantly downregulated in GSE38417 DMD (logFC = -0.45, adj.P<0.001). Deoxygalactonojirimycin, an iminosugar and an FDA/EMA-approved pharmacological chaperone (migalastat/Galafold) for Fabry disease, has been reported to be a specific molecular interactor that stabilizes MYORG protein in skeletal muscle. Conclusions This multi-dataset study further supports the role of MYORG and STRADB as activity-sensitive muscle genes that are robustly downregulated in DMD and LGMD. The pharmacological interaction between migalastat and MYORG provides a mechanistically grounded rationale for investigating this approved agent as an adjunct therapy in muscular dystrophies, in combination with the existing standard of care. This also supports active investigation of iminosugar analogs to target MYORG as potential therapeutics for improving skeletal muscle function in dystrophies, frailty, and sarcopenia.

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2026-05-01 | Myoblast-seeded alginate tubes exacerbate dystrophic features in a mouse model of dysferlinopathy

Introduction: Physical therapy (PT) alone is insufficient to restore lost skeletal muscle tissue in individuals with genetic muscle diseases, such as limb-girdle muscular dystrophy type 2B (LGMD2B). However, PT delivered within a regenerative rehabilitation framework -- one that combines cellular therapies with movement-based interventions has the potential to change the status quo in the field. Therefore, we developed a novel muscle regeneration strategy, which could be augmented by targeted, dosage-adjusted progressive resistance training. This study examined if alginate tubes containing myogenic cells could support in vivo muscle regeneration in a mouse model of LGMD2B. Methods: The technology to generate and implant myogenic alginate tubes was first developed and validated through in vitro experimentation. Using this workflow, we produced 21-gauge alginate tubes composed of 10% sodium alginate and healthy donor myogenic cells. Our laboratory has previously developed a technique known as minimally-invasive muscle embedding (MIME), which is effective in generating donor-cell-derived myogenesis in the mouse tibialis anterior (TA) muscle. In this study, we implanted cellularized alginate tubes into the left TA muscle of four female mice from a mouse model of LGMD2B (dysferlin-deficient) using MIME. Histological evaluation was performed 28 days post-implantation. No statistical analyses were performed due to the exploratory nature and small sample size. Results: Cellularized alginate tubes did not dissolve within host muscle even 28 days post-implantation – we had predicted that the alginate tubes would dissolve within a few days. Furthermore, there was no evidence of donor-cell-derived myogenesis. Unexpectedly, we found that MIME-treated muscles exhibited aggravated dystrophic features, including increased fibrosis, lipid deposition, and muscle fiber size heterogeneity, relative to contralateral control limbs. Discussion: The persistence of alginate constructs and absence of donor myogenesis suggest that delivery systems requiring faster degradation or better host-cell integration may be needed. Despite the unexpected outcome, the model revealed a more severe phenotype than typical LGMD2B mice, offering potential utility in future preclinical testing. Conclusions: Engineered myogenic constructs using alginate tubes failed to promote donor-cell-derived regeneration but may enhance modeling of LGMD2B for basic and preclinical studies. Improvements in construct design and additional testing in healthy and dystrophic mice are warranted. Acknowledgments: Supported by NIH R03HD091648, NIH P2CHD086843 (AR3T Pitch Award), NIH R01AR079884 (subcontract), Wayne State Warrior Funder, and the Jain Foundation. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

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2026-03-23 | DAB2 in LGMD R2: a molecular link between disease progression and lipid dysregulation.

Limb-girdle muscular dystrophy R2 (LGMD R2) is an autosomal recessive disorder caused by dysferlin deficiency, leading to progressive muscle weakness and wasting. The lack of reliable clinical biomarkers has limited disease monitoring and therapeutic evaluation. Here, we identified Disabled-2 (DAB2) as a molecular and clinical indicator of disease state in LGMD R2. Transcriptomic profiling revealed a significant upregulation of DAB2 in induced pluripotent stem cell-derived (iPSC-derived) myotubes from patients, a finding validated in muscle biopsies from 14 dysferlin-deficient individuals and in dysferlin-deficient Bla/J mice, where DAB2 levels increased with disease progression. Importantly, AAV-mediated expression of full-length dysferlin restored DAB2 levels, supporting its value as a dynamic readout of disease activity for both disease monitoring and therapeutic response. Given the established role of DAB2 in clathrin-mediated endocytosis, particularly in LDL receptor internalization and cholesterol homeostasis, and the pathological lipid accumulation reported in LGMD R2, we investigated its contribution to lipid dysregulation. High DAB2 expression paralleled lipid deposition in patient muscles, iPSC-derived myotubes, and mouse tissue, whereas siRNA-mediated DAB2 knockdown reduced lipid accumulation in LGMD R2 myotubes. Collectively, these findings suggest that DAB2 functions as a mechanistic link between dysferlin deficiency, altered lipid handling, and disease severity, and they highlight its potential as a prognostic marker and therapeutic response measure for LGMD R2.

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