Skeletal muscle transcriptomic profile of older adults with high-impact musculoskeletal pain in the study of muscle, mobility and aging (SOMMA).

High-impact musculoskeletal pain (i.e., pain that limits daily activities and function) affects a substantial proportion of older adults and is associated with accelerated mobility decline. While skeletal muscle is central to movement and functional capacity, its molecular contribution to pain-related disability in aging remains poorly understood. We conducted a cross-sectional analysis of baseline data from 742 community-dwelling adults aged 70 years or older from the Study of Muscle, Mobility and Aging (SOMMA). Bulk RNA sequencing was performed on vastus lateralis muscle biopsies. Pain impact was classified using self-reported pain and limitations in activities of daily living. Differential gene expression was examined comparing high-impact pain, low-impact pain, and no pain, with sex-stratified analyses. Pathway enrichment analyses were conducted to identify biological processes associated with high-impact pain. High-impact musculoskeletal pain was associated with a distinct skeletal muscle transcriptomic profile, whereas minimal differences were observed between low-impact pain and no pain. Sex-stratified analyses revealed substantial differences in pain-related gene expression for men and women. In men, high-impact pain was characterized by enrichment of musculoskeletal structural and extracellular matrix pathways. In women, high-impact pain was associated with broader transcriptional alterations involving immune, inflammatory, metabolic, and cytoskeletal processes. High-impact musculoskeletal pain in older adults was associated with sex-dependent skeletal muscle transcriptomic signatures distinct from those observed in low-impact pain. These findings implicate muscle-specific molecular pathways in pain-related functional limitations and highlight the importance of sex-informed approaches to understanding and treating chronic pain in aging.