The general research theme for the lab is: Adaptation of skeletal muscle in health and disease.
Skeletal muscle is the largest tissue in the body and accounts for approximately 40% of body mass. It is well established that decreased strength in humans is correlated with increased mortality and decreased quality of life. It is only recently that research has determined that the skeletal muscle weakness and pathologies associated with chronic diseases are not due simply to decreased activity but arise from other factors that are still poorly defined.
The two major research focus areas are:1) to determine the molecular signaling mechanisms regulating anabolism/protein synthesis in skeletal muscle2) to determine the function of the molecular clock in skeletal muscle and its role in the myopathies seen in chronic diseases.These general aims are approached experimentally by using genetic mouse models [knock outs, conditional knock outs and transgenics] with both in vivo and in vitro measures of muscle phenotype and function.
The use of well-defined physiological systems with newly evolving technologies allows for more mechanistic testing of a molecular function in an integrated system.
Muscle Growth Project: Since the Baar and Esser paper (AJP:Cell, 1999) my lab has been studying anabolic signaling in skeletal muscle with a particular focus on mTOR. We are interested in understanding the upstream regulators of mTOR with more of a focus on mechanical signaling. From this work we have recently identified that REDD2 is a negative regulator of mTOR signaling and is uniquely expressed in skeletal muscle.
Circadian Rhythm Project: The molecular clock mechanism exists in skeletal muscle cells as it does in the brain and other peripheral tissues. We have recently determined that disruption of the molecular clock in skeletal muscle leads to profound structural and functional deficits in the adult mouse. In addition we have found that the Clock factors (CLOCK and BMAL1) transcriptionally regulate MyoD1 in adult skeletal muscle.We have found that clock-compromised mice exhibit altered myofibrillar structure, reduced maximum force and reduced mitochondrial volume.
Ongoing projects include determining 1) the time cues regulating proper expression of the core clock genes Clock and Bmal1, in skeletal muscle; 2) mechanisms by which the core clock genes regulate MyoD1 expression and muscle specific transcriptional targets; and 3) contribution of clock factors to the progression of adult skeletal muscle disease in models of cardiovascular disease, metabolic disease and aging.