Circadian rhythms have long been known to influence behavioral and biological processes such as physical activity and feeding behavior. The fundamental importance of this system, which works to link physiology with the day/night cycle, is underscored by its presence in every known species. Recent studies have identified that most cell types, including skeletal muscle, display circadian oscillations in gene expression and function. While the central clock, the superchiasmatic nucleus (SCN), is considered the master regulator, growing evidence has defined a level of autonomy for the peripheral clocks. In the case of skeletal muscle, there is very little known about circadian rhythms with only a few studies in humans that have demonstrated maximum force generation varies with time of day. There are, however, several lines of evidence that link regulation (entrainment) of core circadian oscillators to the energy and force production driven by locomotor activity. These observations clearly suggest a potentially significant role for the limb musculature to circadian rhythm biology. One of the fundamental core circadian rhythm genes, Bmall (Brain muscle arnt like 1/MOP3), is characterized by its abundant expression in skeletal muscle. Interestingly, mice in which Bmall has been ablated exhibit a significant reduction in voluntary wheel running activity by over 60% as well as the expected loss of circadian behavior (7). Recent results from microarray experiments have identified that Bmall mRNA is significantly increased in skeletal muscle of both humans and rats at 6 hours following an acute bout of high resistance exercise (8) (Zambon, UCSF, personal communication). The studies outlined in this R21 proposal, are designed to test the following hypotheses: 1) skeletal muscle, independent of innervation, displays circadian periodicity in function and 2) appropriate expression of the circadian rhythm genes, in particular Bmall, is necessary for normal skeletal muscle function and phenotype. Results from these studies will be critical in providing the foundation for future studies on the complex interaction between skeletal muscle circadian gene expression, muscle function and physical activity behaviors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Exploratory/Developmental Grants (R21)
Project #
7R21AR050717-03
Application #
7066500
Study Section
Special Emphasis Panel (ZAR1-RJB-A (O1))
Program Officer
Nuckolls, Glen H
Project Start
2003-09-25
Project End
2006-06-30
Budget Start
2005-02-01
Budget End
2006-06-30
Support Year
3
Fiscal Year
2004
Total Cost
$29,488
Indirect Cost
Name
University of Kentucky
Department
Physiology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Andrews, Jessica L; Zhang, Xiping; McCarthy, John J et al. (2010) CLOCK and BMAL1 regulate MyoD and are necessary for maintenance of skeletal muscle phenotype and function. Proc Natl Acad Sci U S A 107:19090-5
McCarthy, John J; Andrews, Jessica L; McDearmon, Erin L et al. (2007) Identification of the circadian transcriptome in adult mouse skeletal muscle. Physiol Genomics 31:86-95
Miller, Brooke H; McDearmon, Erin L; Panda, Satchidananda et al. (2007) Circadian and CLOCK-controlled regulation of the mouse transcriptome and cell proliferation. Proc Natl Acad Sci U S A 104:3342-7
Sullivan, Patrick G; Balke, C William; Esser, Karyn A (2006) Mitochondrial buffering of calcium in the heart: potential mechanism for linking cyclic energetic cost with energy supply? Circ Res 99:109-10