Consistent MYORG and STRADB Downregulation in DMD and LGMD: Rationale for Deoxygalactonojirimycing Repurposing in Dystrophic and Aging Muscle

Abstract

Background: MYORG is an activity-dependent skeletal muscle gene implicated in frailty and sarcopenia. We hypothesized that, if sustained by contractile activity, it should be downregulated in muscular dystrophies, and sought protein-level confirmation of this hypothesis. Methods: We performed a systematic cross-dataset transcriptomic analysis of five GEO microarray datasets of human skeletal muscle, followed by protein-level validation in an independent human dystrophic muscle proteomics dataset (PXD050694). Transcriptomic discovery used GSE3307 (DMD, LGMD2A/B/I, BMD, FSHD, JDM, ALS, AQM versus controls); validation used GSE38417, GSE11681, GSE465, and GSE1007. After NUSE/RLE quality control, arrays were RMA-normalized and differential expression assessed by limma with Benjamini-Hochberg correction. Proteomics data were extracted from a Proteome Discoverer MSF database via SQLite and quantified as MS1 intensity per patient group. Results: In GSE3307, MYORG was significantly downregulated in DMD (logFC=-0.93), LGMD2A (-0.82), LGMD2B (-1.01), and LGMD2I (-1.03; all adj.P<0.01). MYORG downregulation in DMD was replicated in GSE38417 (-1.40) and GSE1007 (-0.80; both adj.P<0.001). Critically, proteomic validation (PXD050694) confirmed that MYORG protein is depleted by 98% in DMD and 89% in BMD relative to controls, a loss far exceeding the transcriptional reduction and indicating additional proteostatic degradation in the dystrophic environment. Deoxygalactonojirimycin (DGJ), the active moiety of the approved chaperone migalastat, is a specific molecular interactor that stabilizes MYORG protein; the profound protein-level depletion provides the strongest mechanistic basis for a pharmacological chaperone strategy targeting residual MYORG rescue in DMD. Conclusions: MYORG is robustly and reproducibly downregulated in DMD and LGMD. Proteomic validation in an independent human dystrophic muscle dataset (PXD050694) confirms that MYORG protein is depleted by 98% in DMD and 89% in BMD relative to controls, establishing that the transcriptional signal is accompanied by profound protein-level loss and strengthening the rationale for a pharmacological chaperone strategy. The migalastat-MYORG interaction provides a mechanistic rationale for repurposing this approved agent and for iminosugar analogs targeting MYORG in dystrophies, frailty, and sarcopenia.