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.
Sarangarajan, R., Iyengar, K.
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