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Chronic circadian misalignment accelerates sarcopenia progression in mice

ABSTRACT: In today's 24/7 society, circadian misalignment caused by environmental and lifestyle factors is associated with various adverse health consequences, underscoring the need to understand tissue-specific pathology. A potential association of environmental circadian misalignment with sarcopenia, or accelerated loss of skeletal muscle strength and mass, is poorly documented. Here, we exposed wild-type C57BL/6J male mice to a chronic (64 weeks) jet lag (CJL) paradigm. CJL caused significant reductions in muscle strength and weight relative to untreated mice. Transcriptomic and histological analysis showed activation of TWEAK/Fn14 signaling and reduced myofiber cross-sectional area, hallmark features of sarcopenia. Furthermore, CJL mice showed increased centrally nucleated fibers, myosin heavy chain co-expressing fibers, and myogenic gene expression, suggesting that insufficient muscle regeneration likely contributes to muscle atrophy. These findings demonstrate that circadian misalignment is an independent risk factor for sarcopenia, underscoring circadian rhythms as a key regulator and actionable target for sarcopenia prevention.

ORGANISM(S): Mus musculus

PROVIDER: GSE296198 | GEO | 2025/12/09

REPOSITORIES: GEO

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Project description:The degenerative loss of muscle associated with aging leading to muscular atrophy is called sarcopenia. Currently, practicing regular physical exercise is the only efficient way to delay the onset of sarcopenia. To identify therapeutic targets to suppress the symptoms of aging, there is a need for in vivo model organisms of accelerated muscle degeneration and atrophy. The zebrafish harbors hallmarks of aging, notably mitochondrial dysfunction, telomeres shortening and accumulation of senescent cells. Unfortunately, zebrafish aged slowly, and no specific zebrafish models of accelerated muscle atrophy associated with aging or sarcopenia are currently available. We have developed a new genetic tool to efficiently accelerate muscle fibers degeneration and muscle tissue atrophy in zebrafish larvae and adults. We used a gain-of-function strategy with a molecule that has been shown to be necessary and sufficient to induce muscle atrophy and a sarcopenia phenotype in mammals: Atrogin1 (also named Fbxo32). We report the generation, validation, and characterization of a zebrafish genetic model of accelerated muscle atrophy, the sarcofish. We demonstrated that specific expression of Atrogin1 in skeletal muscle tissue induces a muscle atrophic phenotype associated with locomotion dysfunctions in both larvae and adult fish. We identified that degradation of the myosin light chain as an event occurring before the degeneration of muscle fibers. Biological processes associated with muscle aging such as inflammation, proteolysis, apoptosis and stress response are upregulated in the sarcofish. Surprisingly, we observed a strong correlation between muscle fibers degeneration and a reduction of neuromuscular junctions in the peripheral nervous system, as well as neuronal cell bodies in the spinal cord, suggesting that muscle atrophy could underly a neurodegenerative phenotype in the central nervous system. Finally, while sarcofish larvae harbor regeneration of muscle fibers, spinal neurons and recover locomotive functions, adult sarcofish have impaired regenerative capacities as observed in mammals during muscle aging. In the future, the sarcofish could open new strategies in the fight against the sarcopenia disease to test therapeutic molecules aiming to treat or alleviate the symptoms of muscle aging.

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Chronic circadian misalignment accelerates sarcopenia progression in mice

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