Molecular clock and skeletal muscle weakness

Skeletal muscle weakness has long been known to contribute to morbidity and mortality in aging and other diseases. Single fiber studies from different models of weakness in humans and rodents have demonstrated reduced force implicating alterations in myofilament protein expression, post-translational modifications and sarcomere organization. Our recent work in the emerging area of circadian rhythms and the molecular clock in skeletal muscle holds potential to provide insight into mechanisms of weakness. Most recently we generated an inducible line of mice in which Bmal1 is deleted only in adult skeletal muscle following tamoxifen treatment (iMSBmal1-/-). We observed progressive declines in cage activity, voluntary wheel activity and EDL maximum force and passive tension were significantly reduced with no loss in muscle mass. We have identified circadian expression of transcription factors important for muscle (Srf, Sox6 and Tead4) and we found that circadian expression of these genes was disrupted in the muscle of iMSBmal1-/-mice. These observations support our hypothesis that the molecular clock in skeletal muscle directly regulates expression of a network of important transcription factors (muscle clock controlled genes) and when the molecular clock is disrupted, this leads to downstream effects on sarcomere gene expression, sarcomere structure and muscle mechanical function. In addition to work on the molecular clock, my lab and others have demonstrated that scheduled physical activity can function as an environmental non-photic time cue for the skeletal muscle molecular clock. This discovery highlights a new mechanism for physical activity and provides the basis for our second hypothesis: Time of exercise will act as a therapeutic intervention to slow the progression of muscle weakness in aging. These two hypotheses will be tested in the following three specific aims. Specific Aim 1: To determine whether the myogenic transcription factors, Srf, Sox6, Tead4 are direct molecular clock controlled genes in skeletal muscle. Specific Aim 2: To determine the mechanism by which active and passive tension is reduced in skeletal muscle fibers of iSMBmal1-/- mice. Specific Aim 3: To determine whether time of exercise modifies the rate of progression of muscle weakness with aging.