HARRTC Fellow - Dr. Kevin Zwetsloot's
Research Plan
 Sarcopenia is the loss of muscle mass and strength commonly associated with aging. Nearly 45% of aged individuals in the U.S. suffer from sarcopenia (as defined by muscle loss from adulthood to advanced age). Reports estimate that the rate of muscle loss is approximately 10% per decade, after the age of 50, while atrophy (a reduction in muscle fiber size) resulting from immobilization occurs at a much faster rate. Immobilization-induced atrophy and sarcopenia are additive. More importantly, recovery from a loss in muscle mass is impaired or absent in aged muscle. Sarcopenic individuals often undergo surgery and the hospitalization that ensues can accelerate the onset of physical frailty. This is clinically relevant because most often elderly individuals fail to return to preoperative levels of muscle function and self-sufficiency.
Skeletal muscle displays a remarkable ability to respond and adapt to a variety of physiological stimuli/conditions. Our laboratory (under the direction of Frank W. Booth, Ph.D.) uses a model of rat hindlimb immobilization to investigate the mechanisms involved in skeletal muscle atrophy and regrowth. Previously, we have demonstrated that 10 days of hindlimb immobilization induced skeletal muscle atrophy in both young and aged rats; however only the young skeletal muscle displayed any significant regrowth when activity was resumed. Little is known about the mechanisms that regulate skeletal muscle loss and impaired/failed regrowth associated with aging and even less is known as to why physical rehabilitation of aged skeletal muscle is less effective compared to young. We believe that the rapid atrophy and impaired/failed regrowth in aged skeletal muscle both contribute to the onset and severity of sarcopenia, which can lead to physical frailty.
Skeletal muscle contains a population of cells, including satellite cells, called muscle precursor cells (MPCs). MPCs possess myogenic potential and are required for growth, repair/regeneration, and hypertrophy of skeletal muscle. MPCs isolated from whole skeletal muscle and grown in culture display robust proliferation and are able to differentiate into multi-nucleated myotubes; however, MPCs isolated from aged skeletal muscle exhibit impaired activation and proliferation compared to MPCs isolated from young skeletal muscle.
Our laboratory utilizes MPCs grown in culture to investigate several mechanisms that have been implicated in the regulation of skeletal muscle atrophy and regrowth. Cyclins and cyclin-dependent kinases (Cdk) are essential for cell cycle control and the expression of several Cdk inhibitors induces cell cycle withdrawal. My research focuses on the expression and regulation of Cdk inhibitors in cultured MPCs and more specifically their role in the proliferation of MPCs isolated from skeletal muscle of young and old rats subjected to immobilization or recovery from immobilization. We hypothesize that Cdk inhibitors contribute to the atrophy and impaired/failed regrowth observed in aged skeletal muscle. Therefore, investigating Cdk inhibitors in MPCs in vitro may elucidate the mechanisms responsible for sarcopenia and impaired/failed regrowth observed in aged skeletal muscle after immobilization-induced atrophy. Further, understanding these mechanisms may lead to the development of treatments and/or prevention of this condition.
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