A new study in mice highlights the critical role of muscle Brain and muscle Arnt-like protein-1 (BMAL1)—a key component of the circadian clock—on muscle homeostasis, with further implications on systemic health and lifespan.

The circadian clock, a molecular clock present in virtually all body cells, controls many cellular and physiological processes. BMAL1 acts as an essential component of this molecular oscillator by interacting with another transcription factor—circadian locomoter output cycles protein kaput (CLOCK)—to regulate the daily cellular transcriptional program. Prior work has shown that Bmal1 knockout mice (KO) have a reduced lifespan (~37 weeks) and display various symptoms of premature aging, including sarcopenia as well as defective glucose homeostasis. Genetic approaches to rescue Bmal1 expression in the brain, liver or epidermal tissues of Bmal1 KO mice have not resulted in an extension of lifespan, suggesting that Bmal1 function in other tissues is important for longevity.

Here, Gutierrez-Monreal et al. used an adeno-associated virus (AAV) approach to rescue Bmal1 expression specifically in the skeletal muscles of Bmal1-KO mice. Survival analyses showed that muscle-specific Bmal1-KO+AAV mice had an extended lifespan, with 88.9% of them surviving through 40 weeks, while only 44.2% of Bmal1-KO mice survived over the same period.

Bmal1 rescue also markedly improved muscle strength, mobility and glucose tolerance in Bmal1-KO+AAV mice compared to Bmal1-KO mice, despite no effects on muscle mass or fiber size. Transcriptomics and proteomics on skeletal muscles, together with RNA sequencing of other tissues, indicated that rescuing the expression of Bmal1 in the muscles of Bmal1-KO mice improved the pathways regulating glucose metabolism while reducing inflammation in muscles and peripheral tissues.

Together, these findings demonstrate the critical role of the circadian clock in skeletal muscle function and metabolism, and the impact of skeletal muscle homeostasis on systemic health and aging.

Original reference: Gutierrez-Monreal, M.A. et. al. JCI Insight 9, e174007 (2024)