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 and voluntary wheel activity and we determined that the muscles were weak with significant declines in maximum force and passive tension. To begin to identify the molecular mechanism(s) underlying weakness in this model, we have identified circadian expression of transcription factors important for muscle (Srf, Sox6 and Tead1) and we found that 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, Tead1 are direct molecular clock controlled genes in skeletal muscle.
Specific Aim 2 : To determine the sarcomeric changes through 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. The results of these studies will provide new insight into mechanisms that link disrupted circadian rhythms and muscle weakness. Since aging and many chronic diseases are known to disrupt molecular clock function these findings may also provide novel new targets for therapeutic strategies.
Skeletal muscle weakness has long been known to contribute to morbidity and mortality in aging and other diseases. The experiments outlined in this grant will test the hypothesis that the molecular clock in skeletal muscle regulates a network of important transcription factors that are important for maintenance of muscle structure and function. Additionally we will test whether time of exercise will act as a therapeutic intervention to slow the progression of muscle weakness in aging.
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