Calcineurin in Prostaglandin Mediated Muscle Growth

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DESCRIPTION (provided by applicant): A loss of skeletal muscle functional capacity occurs in disease, disuse and aging mostly attributable to a loss of muscle mass. Such losses of muscle mass contribute to weakness, impaired mobility and/or respiratory function, low quality of life and high health care costs. Skeletal muscle is strongly dependent on mechanical signals for maintenance and growth. The signal transduction pathways that link muscle use to subsequent growth are not well understood. Prostaglandins (PG) are known mediators of growth in many cell types including skeletal muscle and are synthesized and released in response to mechanical stimuli. The mechanism by which prostaglandins lead to growth in skeletal muscle is largely unknown and is the focus of this proposal. We hypothesize that the prostaglandin PGF2a leads to muscle growth through a Calcineurin/NFAT dependent signaling pathway. This hypothesis is based on our identification of PGF2a as a novel activator of this pathway. This proposal has three overall goals: 1) to study the role of calcineurin in modulating muscle growth; 2) to study the role of calcineurin and its downstream effector NFAT in regulating the expression of COX2. COX2 is a key enzyme necessary for the synthesis of prostaglandins; 3) to determine if prostaglandins and IGF-1 work together or independently to regulate muscle growth in response to mechanical stimuli. We will utilize mechanical stretch of cultured myotubes in the presence and absence of pharmacologic and genetic inhibitors/activators of the Calcineurin/NFAT pathway to study the regulation of muscle growth in response to mechanical stretch. The work will be extended to encompass studies of mechanically stimulated muscle growth in vivo in order demonstrate whether the proposed pathways are physiologically active. Together, these studies will define a signal transduction pathway by which adult skeletal muscle growth can be regulated in response to muscle use. Given the number of clinical conditions in which loss of muscle mass occurs, understanding the molecular pathways regulating myofiber growth is important for developing new avenues of rehabilitative therapy for manipulating this growth process in disease, disuse and aging.