Chronic circadian misalignment accelerates sarcopenia progression in mice

TAKASHI SEYA^1,2Nobuya Koike¹Naoki Okubo^1,2Yasuhiro Umemura¹Yoshiki Tsuchiya¹Kazuya Yabumoto¹Yasuhiro Endo¹Kanako Iinuma^1,2Akiyo Kakibuchi¹Akira Sugimoto¹Kenji Takahashi²Seung-Hee Yoo³Zheng Chen³Kazuhiro Yagita^1*

• ¹Department of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine, Kyoto, Japan
• ²Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
• ³Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, TX, United States

Abstract Introduction: In today's 24/7 society, circadian misalignment caused by environmental and lifestyle factors is associated with various adverse health consequences. Understanding tissue-specific pathology is required to counter this growing public health challenge. A potential association of environmental circadian misalignment with sarcopenia, or accelerated loss of skeletal muscle strength and mass, is poorly documented. Methods: 14-week-old wild-type C57BL/6J male mice were exposed to a chronic jet lag (CJL) paradigm consisting of an 8-hour phase advance every 4 days (the ADV group) or a fixed light-dark cycle (the LD group) for 64 weeks. Grip strength was measured during the experiment, and hindlimb muscle weight was assessed after the 64-week CJL. In addition, transcriptomic and histological analysis of the hindlimb muscles were performed in all animals. Results: ADV mice exhibited significant reductions in grip strength and muscle weight relative to LD mice. Transcriptomic and histological analyses showed activation of TWEAK/Fn14 signaling and reduced myofiber cross-sectional area, hallmark features of sarcopenia, in the ADV group. Somewhat surprisingly, ADV mice showed increased centrally nucleated fibers, myosin heavy chain co-expressing fibers, and myogenic gene expression, suggesting that compensatory muscle regeneration and remodeling processes are activated but remain insufficient to counter muscle atrophy. Conclusion: These findings demonstrate that circadian misalignment is a potential risk factor for sarcopenia, underscoring circadian rhythms as a key regulator and actionable target for sarcopenia prevention.