The ectopic olfactory receptor OR10J5 counteracts skeletal muscle senescence and age-related decline

Skeletal muscle aging is characterized by a progressive decline in skeletal muscle mass and function, yet the molecular factors driving this deterioration remain incompletely understood. We identify the ectopic olfactory receptor OR10J5 as a regulator of skeletal muscle senescence and aging. Or10j5 mRNA expression is reduced across cellular models of senescence and muscle atrophy, mouse models of muscle atrophy, and naturally aged skeletal muscle. Genetic ablation of Or10j5 exacerbates age-associated muscle loss and functional decline in mice, accompanied by increased senescence-associated changes. Conversely, pharmacological activation of OR10J5 with lyral attenuates senescence- and atrophy-associated phenotypes and improves muscle mass and physical performance in naturally aged wild-type, but not Or10j5-deficient mice. Lyral similarly attenuates senescence- and atrophy-associated phenotypes in human embryonic stem cell-derived myotubes. Mechanistically, lyral activates OR10J5-dependent cAMP-PKA-CREB signaling and modulates transcriptional programs related to myogenesis, mitochondrial biogenesis, and cellular senescence. Together, these findings support OR10J5 activation as a potential strategy to counter age-related muscle decline.