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.