Intrinsic muscle clock is necessary for musculoskeletal health.
CONCLUSIONS
The endogenous molecular clock in skeletal muscle is necessary for maintenance of phenotype and function. 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. 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. iMSBmal1(-/-) mice develop increased bone calcification and decreased joint collagen, which in combination with the functional changes in skeletal muscle results in altered gait. This study uncovers a fundamental role for the skeletal muscle clock in musculoskeletal homeostasis with potential implications for ageing.
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.
Center for Muscle Biology, University of Kentucky, Lexington, KY, USA.|Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA.
Elizabeth A
EA
Schroder
Center for Muscle Biology, University of Kentucky, Lexington, KY, USA.|Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA.
Brianna D
BD
Harfmann
Center for Muscle Biology, University of Kentucky, Lexington, KY, USA.|Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA.
Xiping
X
Zhang
Center for Muscle Biology, University of Kentucky, Lexington, KY, USA.|Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA.
Ratchakrit
R
Srikuea
Center for Muscle Biology, University of Kentucky, Lexington, KY, USA.
Jonathan H
JH
England
Center for Muscle Biology, University of Kentucky, Lexington, KY, USA.|Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA.
Brian A
BA
Hodge
Center for Muscle Biology, University of Kentucky, Lexington, KY, USA.|Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA.
Yuan
Y
Wen
Center for Muscle Biology, University of Kentucky, Lexington, KY, USA.|Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA.
Lance A
LA
Riley
Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA.
Qi
Q
Yu
Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA.
Alexander
A
Christie
Center for Muscle Biology, University of Kentucky, Lexington, KY, USA.|Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA.
Jeffrey D
JD
Smith
Center for Muscle Biology, University of Kentucky, Lexington, KY, USA.
Tanya
T
Seward
Center for Muscle Biology, University of Kentucky, Lexington, KY, USA.|Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA.
Erin M
EM
Wolf Horrell
Center for Muscle Biology, University of Kentucky, Lexington, KY, USA.|College of Health Sciences, University of Kentucky, Lexington, KY, USA.
Jyothi
J
Mula
Center for Muscle Biology, University of Kentucky, Lexington, KY, USA.|College of Health Sciences, University of Kentucky, Lexington, KY, USA.
Charlotte A
CA
Peterson
Center for Muscle Biology, University of Kentucky, Lexington, KY, USA.|College of Health Sciences, University of Kentucky, Lexington, KY, USA.
Timothy A
TA
Butterfield
Center for Muscle Biology, University of Kentucky, Lexington, KY, USA.|Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA.
Karyn A
KA
Esser
D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001683:Biological Clocks; D001842:Bone and Bones / Q000473:pathology; D002114:Calcinosis / Q000235:genetics; D003094:Collagen / Q000378:metabolism; D005355:Fibrosis; D005684:Gait; D007596:Joints / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype
D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D003094:Collagen