Skeletal muscle regrowth is a fundamental process that allows the recovery of mass after a bout of atrophy induced by physical inactivity. Unfortunately, under some circumstances, such as aging, hypertension, or diabetes, the skeletal muscle does not respond to increases in mechanical load by increasing muscle mass. The long term objective is to determine the cellular/molecular mechanisms that regulate muscle regrowth under healthy conditions, and determine if the mechanisms are dysfunctional in conditions where skeletal muscle does not regrow after a bout of atrophy. Increases in muscle mass are regulated at multiple levels, including the transcriptional, translational, and post- translational level. Although, key molecular mechanisms that regulate the recovery of muscle from a bout of atrophy remain undefined, it is well known that endogenous growth factors play an integral role in stimulating muscle growth. Recently, insulin-like growth factor (IGF-I) has been used to induce skeletal muscle hypertrophy, to rescue lost muscle mass in aged animals and to treat neuromuscular diseases such as muscular dystrophy and amyotrophic lateral sclerosis. Unfortunately, it is unclear how IGF-I is impacting beneficial effects on the skeletal muscle. Currently, the transcriptional mechanisms that impact gene expression during muscle regrowth are not completely defined, and further the potential interaction of IGF-I with these mechanisms has never been explored. The understanding of the mechanisms activated by IGF-I is of fundamental importance to the muscle biology field, since it will be difficult to use IGF-I in human medicine, due to the numerous undesired side effects of IGF-I, including cancer. One potential way to circumvent the side effects is to understand the cellular mechanisms by which IGF-I alters skeletal muscle, and then modulate these mechanisms through pharmacological means.
Specific Aim 1 will delineate the cis elements and the transcription factors necessary for transcriptional activation of the skeletal a-actin gene during skeletal muscle regrowth. Unfortunately to date, no studies have examined any cis-elements and/or trans-factors that regulate transcriptional activation of any gene during recovery from a bout of skeletal muscle atrophy.
Specific Aim 2 will determine the role IGF-I, has on the transcriptional activation of the skeletal a-actin gene through specific cis-elements and transcription factors during skeletal muscle regrowth. The overall goal is to determine the role IGF-I may have in activating transcriptional activity during muscle regrowth.
