Circadian rhythms, the molecular clock, and skeletal muscle

Abstract

Circadian rhythms are the approximate 24-h biological cycles that function to prepare an organism for daily environmental changes. They are driven by the molecular clock, a transcriptional:translational feedback mechanism that in mammals involves the core clock genes Bmal1, Clock, Per1/2, and Cry1/2. The molecular clock is present in virtually all cells of an organism. The central clock in the suprachiasmatic nucleus (SCN) has been well studied, but the clocks in the peripheral tissues, such as heart and skeletal muscle, have just begun to be investigated. Skeletal muscle is one of the largest organs in the body, comprising approximately 45% of total body mass. More than 2300 genes in skeletal muscle are expressed in a circadian pattern, and these genes participate in a wide range of functions, including myogenesis, transcription, and metabolism. The circadian rhythms of skeletal muscle can be entrained both indirectly through light input to the SCN and directly through time of feeding and activity. It is critical for the skeletal muscle molecular clock not only to be entrained to the environment but also to be in synchrony with rhythms of other tissues. When circadian rhythms are disrupted, the observed effects on skeletal muscle include fiber-type shifts, altered sarcomeric structure, reduced mitochondrial respiration, and impaired muscle function. Furthermore, there are detrimental effects on metabolic health, including impaired glucose tolerance and insulin sensitivity, which skeletal muscle likely contributes to considering it is a key metabolic tissue. These data indicate a critical role for skeletal muscle circadian rhythms for both muscle and systems health. Future research is needed to determine the mechanisms of molecular clock function in skeletal muscle, identify the means by which skeletal muscle entrainment occurs, and provide a stringent comparison of circadian gene expression across the diverse tissue system of skeletal muscle.

Keywords: Bmal1; Clock; MyoD1; insulin signaling; metabolism; sarcomere.

Figure 1

Simplified cartoon of molecular clock components in muscle. This cartoon highlights the role of CLOCK:BMAL1 as part of the core molecular clock and also illustrates their role directly targeting transcription of genes important for muscle-specific function.

Figure 2

Cartoon depicting time-of-day coordination between skeletal muscle and liver metabolism for the regulation of systems glucose homeostasis. The dark phase/fed phase for mice is characterized by higher insulin sensitivity in skeletal muscle/liver and decreased hepatic glucose production. The light phase/fasting phase for mice is characterized by reduced insulin sensitivity in skeletal muscle/liver and increased hepatic glucose production.