Intrinsic muscle clock is necessary for musculoskeletal health

Abstract

Key pointsr The endogenous molecular clock in skeletal muscle is necessary for maintenance of phenotype and function.r Loss of Bmal1 solely from adult skeletal muscle (iMSBmal1 −/− ) results in reductions in specific tension, increased oxidative fibre type and increased muscle fibrosis with no change in feeding or activity.r Disruption of the molecular clock in adult skeletal muscle is sufficient to induce changes in skeletal muscle similar to those seen in the Bmal1 knockout mouse (Bmal1 −/− ), a model of advanced ageing. r This study uncovers a fundamental role for the skeletal muscle clock in musculoskeletal homeostasis with potential implications for ageing.Abstract Disruption of circadian rhythms in humans and rodents has implicated a fundamental role for circadian rhythms in ageing and the development of many chronic diseases including diabetes, cardiovascular disease, depression and cancer. The molecular clock mechanism underlies circadian rhythms and is defined by a transcription-translation feedback loop with Bmal1 encoding a core molecular clock transcription factor. Germline Bmal1 knockout (Bmal1 KO) mice have a shortened lifespan, show features of advanced ageing and exhibit significant weakness with decreased maximum specific tension at the whole muscle and single fibre levels. We tested the role of the molecular clock in adult skeletal muscle by generating mice that allow for the inducible skeletal muscle-specific deletion of Bmal1 (iMSBmal1). Here we show that disruption of the molecular clock, specifically in adult skeletal muscle, is associated with a muscle phenotype including reductions in specific tension, increased oxidative fibre type, and increased muscle fibrosis similar to that seen in the Bmal1 KO mouse. Remarkably, the phenotype observed in the iMSBmal1 −/− mice was not limited to changes in muscle. Similar to the germline Bmal1 KO mice, we observed significant bone and cartilage changes throughout the body suggesting a role for the skeletal muscle molecular clock in both the skeletal muscle niche and the systemic milieu. This emerging area of circadian rhythms and the molecular clock in skeletal muscle holds the potential to provide significant insight into intrinsic mechanisms of the maintenance of muscle quality and function as well as identifying a novel crosstalk between skeletal muscle, cartilage and bone.

The skeletal muscle circadian clock: current insights

“…50 On the other hand, clock gene disruption hardly affects muscle architecture and strength in young and adult mice. 50,52,56 The effects of muscle clock disruption might be highlighted by aging, since the skeletal muscle of aged im-Bmal KO mice is fibrotic, has reduced force, and is accompanied by bone calcification, although such phenotypes are not evident in younger im-Bmal KO mice. 52 Aging-related systemic changes such as the denervation of motor units, oxidative damage, as well as anabolic resistance and molecular clock disruption caused by shift work, jet lag, and sleep disorders might additively increase risk for poor skeletal muscle health among aged populations.…”

“…Schroder et al estimated that in Dyar et al's study, Bmal1-negative myonuclei could have been diluted by adding Bmal1-positive nuclei after tamoxifen administration. 52 Regardless, the Bmal1 mRNA content in skeletal muscle remarkably decreased in both studies. The second Figure 2 Several zeitgebers work for appropriate oscillation of skeletal muscle clock.…”

“…50 On the other hand, Schroder et al found reduced specific tension and increased muscle fibrosis in a similar im-Bmal1 KO model after 58 weeks of tamoxifen treatment. 52 They also found significant bone calcification and decreased joint collagen at that age, suggesting that the muscle clock functions in both skeletal muscle and systemic tissues via an endocrine/paracrine function. 52 Regarding the discrepancies in the results of the studies by Dyar et al and Schroder et al, Schroder et al noted that differences in experimental design might have been the cause.…”

“…52 They also found significant bone calcification and decreased joint collagen at that age, suggesting that the muscle clock functions in both skeletal muscle and systemic tissues via an endocrine/paracrine function. 52 Regarding the discrepancies in the results of the studies by Dyar et al and Schroder et al, Schroder et al noted that differences in experimental design might have been the cause. 52 Tamoxifen was injected into mice at 8 weeks of age (Dyar et al), when satellite cell fusion to myofibers is still enhanced, and into mice aged between 12 and 16 weeks (Schroder et al).…”

“…52 Regarding the discrepancies in the results of the studies by Dyar et al and Schroder et al, Schroder et al noted that differences in experimental design might have been the cause. 52 Tamoxifen was injected into mice at 8 weeks of age (Dyar et al), when satellite cell fusion to myofibers is still enhanced, and into mice aged between 12 and 16 weeks (Schroder et al). Schroder et al estimated that in Dyar et al's study, Bmal1-negative myonuclei could have been diluted by adding Bmal1-positive nuclei after tamoxifen administration.…”