Muscle development in childhood and muscle regeneration in adults are dynamic processes that are necessary for reaching and maintaining optimal muscle mass and strength throughout life. Muscle repair after injury relies on stem cells (termed satellite cells), which when activated undergo sequential proliferation, differentiation, and fusion with existing myofibers. Satellite cell activity is controlled by complex signals mediated by cell-cell contact, by growth factors, and by hormones, which interact with genetic programs regulated by myogenic transcription factors. The physiologically critical loss of muscle mass and strength that occurs in aging and with chronic disease, termed sarcopenia, affects over 25% of elderly individuals, and accounts for medical costs in the billions. Therapy for sarcopenia is inadequate, primarily because mechanisms responsible for limiting muscle loss have not been elucidated. Insulin-like growth factors (IGFs) play key roles in muscle development and help coordinate muscle repair after injury. IGF actions can counteract inhibitory effects of other signaling molecules on muscle differentiation, and thus represent potentially powerful anabolic agents to reduce or reverse sarcopenia. This project will focus on mechanisms that stimulate muscle differentiation and repair through interactions with pathways regulated by the IGFs, with the goal of using this knowledge to promote long-term enhancement of muscle for therapeutic benefit. The following Specific Aims are proposed to develop these ideas: 1. To define interactions between the IGF-activated PI3-kinase - Akt signaling pathway and p38- regulated pathways. Goals are to delineate biochemical mechanisms that mediate potential cross talk and also define unique functions of each of these networks to promote muscle differentiation. 2. To elucidate mechanisms controlling Igf2 gene transcription during muscle differentiation. Goals are to determine if a putative muscle enhancer mapping >100 kb 3' to the Igf2 gene mediates Igf2 transcriptional activity during muscle differentiation in vitro, and during muscle growth and repair in vivo, and integrates signals from different environmental and genetic programs to regulate the first step in an IGF2-driven autocrine - paracrine muscle differentiation and growth pathway. Proposed studies have the potential to identify new treatment strategies for sarcopenia by establishing mechanisms to facilitate and coordinate activities of critical signal transduction networks that enhance muscle differentiation and stimulate myofiber formation.
A major impediment in developing effective treatments for sarcopenia is lack of knowledge about fundamental relationships between critical signal transduction networks activated by hormones and growth factors, and intrinsic muscle regulatory programs controlled by myogenic transcription factors. As IGF actions play key roles in muscle regeneration following injury, and in sustaining muscle mass during aging and in disease, dissecting the biochemical mechanisms by which IGF-activated signaling pathways interact with myogenic regulatory proteins has potential therapeutic implications. Thus, understanding IGF actions in muscle should yield new insights that will define ways to facilitate muscle regeneration and reverse sarcopenia through selective manipulation of distinct signaling cascades.
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