Mechanical disruption of caveolin signaling complexes

Burkholder, Thomas

Abstract

Healthy and functional skeletal muscle is essential to both life and lifestyle. This mechanical tissue is necessary for respiration, ingestion, locomotion and all the activities of daily life. The growth and maintenance of skeletal muscle is strongly affected by mechanical signals. Stretch is a particularly mediator of skeletal muscle growth and maintenance. Passive stretch of muscle in vivo, in isolation or in vitro results in rapid release of several growth factors, activation of signaling cascades, increase in protein synthesis and hypertrophy. This response is essential to muscle maintenance and growth. Disruption of the mechanical signaling pathways results in muscular dystrophies of varying severity. While stretched induced growth can be mimicked by application of exogenous growth factors, it remains unclear what causes that initial release. This project proposes to investigate the initial mechanism of mechanotransduction by pursuing two alternative membrane related mechanisms. As a muscle fiber changes length, its membrane is forced to change its configuration. This constraint requires an increase in cell surface area with stretch that may be accomplished by unfolding of membrane caveolae and folds. Unfolding of membrane structures may disturb regulatory inhibitions between the membrane bound caveolin-3 and several associated signaling pathways. Hypothesis: mechanical perturbation of the cell membrane signals stretch induced growth by dis- inhibition of caveolin associated proteins. This project proposes to use mechanical and chemical disruption of caveolar structures to identify signaling pathways inhibited by caveolin and leading to muscle growth. This will clarify our understanding of how mechanical signals result in muscle growth and may provide a foundation from which to treat the muscular dystrophies.