Ca Induced Mitochondrial Biogenesis and P38 MAPK

Washington University, Saint Louis MO

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Abstract

DESCRIPTION (provided by applicant): The incidence of obesity and Type II diabetes is growing at epidemic proportions. Recent findings suggest that low skeletal muscle oxidative capacity and mitochondrial dysfunction are linked to the development of these disease states. Although it has been known for approximately 40 years that exercise can lead to increases in skeletal muscle mitochondrial biogenesis and the capacity to oxidize substrates many individuals are unwilling or unable to exercise at a high enough intensity to induce these adaptations. A clear understanding of the mechanisms through which exercise induces mitochondrial biogenesis could lead to treatments which reverse or prevent the development of obesity and the related metabolic abnormalities. The goal of the proposed research is to examine the role of p38 MAPK in Ca2+ induced mitochondrial biogenesis. First, through the use of specific pharmacological inhibitors and/or siRNA technology it will be determined if p38 MAPK inhibition results in an attenuation in Ca2+ mediated increases in mitochondrial enzyme protein abundance and mRNA expression in L6 muscle cells. Secondly, it will determined if increases in the abundance of PGC-1 protein mediates the initial increase in Ca2+ induced mitochondrial biogenesis or whether this process is controlled through the p38 MAPK dependent phosphorylation/activation of PGC-1.