Integrative Multi-Omics Analysis Reveals Molecular Signatures of Age-Related Decline in Vervet Leg Skeletal Muscle

Abstract

Age-related decline in skeletal muscle function, often manifesting as slower gait speed, contributes significantly to frailty and loss of independence. To uncover the molecular basis of this decline, we investigated coordinated changes across the transcriptome, miRNome, and methylome in vastus lateralis muscle from female vervet monkeys (Chlorocebus aethiops sabaeus), contrasting middle-aged animals with normal gait speed versus older animals with declining gait speed. Through multi-omics integration, we identified a molecular signature that sharply distinguishes these two groups. This signature involves key regulatory molecules, including miR-181a-5p, miR-320b and miR-425 control of SYNCRIP, miR-193b-3p regulation of MCL1 and PLAU, as well as a multi-omic regulatory network governing ZNF274 and ANP32E gene expression, and altered levels of mRNAs such as VEZT. Functional annotation implicates miRNA signatures with inverse expression of their mRNA targets operating within systems of skeletal muscle biology, metabolism, and potential immune-inflammation mechanisms. Collectively, these findings reveal an interconnected network of epigenetic, post-transcriptional, and transcriptional alterations associated with impaired muscle function during aging. This molecular signature provides novel insights into potential mechanisms driving sarcopenia and highlights specific molecules as potential targets for interventions aimed at preserving muscle health.