MYORG and STRADB as Activity-Dependent Therapeutic Targets for Frailty Prevention: Discovery and Cross-Cohort Validation in Aging Skeletal Muscle

Abstract

BackgroundSkeletal muscle aging exhibits substantial heterogeneity, with some individuals maintaining robust function into advanced age while others develop sarcopenia and frailty. Whether molecular signatures distinguishing these trajectories reflect biological aging or modifiable factors, such as physical activity, remains unclear. MethodsAn integrated discovery-validation study was conducted on skeletal muscle transcriptomes. Discovery analysis used the GSE144304 dataset comprising vastus lateralis biopsies from young adults (n=26, aged 18-30 years), fit elderly (n=30, aged 65-80 years with preserved function), and frail elderly (n=24, aged 65-80 years stratified by grip strength). Top 10 most significantly altered genes were validated across five independent transcriptomic studies (n=184 total) strategically selected to represent distinct activity contexts: activity-controlled aging, sedentary aging, mixed-activity aging, disease-impaired aging, and exercise intervention. Expression of two established atrogenes were examined (FBXO32/Atrogin-1 and TRIM63/MuRF-1) as benchmarks. ResultsDiscovery analysis identified 10 genes with profound age-related changes (adjusted p 1.3). Cross-dataset validation revealed striking activity-dependence: genes downregulated with aging in sedentary populations (MYORG, STRADB) showed maintained or increased expression in active elderly individuals (80% validation rate, r = 0.75-0.82 with activity level). In contrast, established atrogenes showed poor replication (25-50%) and context-dependent patterns. C4ORF54 expression strongly correlated with grip strength (r = 0.68, p < 0.001), with age effects disappearing after phenotype adjustment, indicating purely phenotype-mediated expression. Critically, sedentary versus active aging datasets showed opposing transcriptional patterns (r = -0.68), demonstrating that activity confounds conventional age-based signatures. ConclusionsMolecular signatures distinguishing fit from frail aging predominantly reflect physical activity levels rather than inevitable biological processes. MYORG and STRADB emerge as activity-responsive biomarkers of muscle health, while C4ORF54 serves as an indicator of functional capacity. These findings challenge conventional atrogene paradigms and suggest that exercise-responsive AMPK signaling pathways represent immediately translatable therapeutic targets for preserving muscle function in older adults.