Skeletal muscle wasting, exercise intolerance and insulin resistance contribute significantly to morbidity and mortality whereas exercise training improves muscle function, circumventing these pathologies. Activation of p38 mitogen-activated protein kinase (MAPK) in adult skeletal muscle has been implicated in these opposing processes, but the underlying mechanism remains elusive. We have recently shown that muscle-specific p383 knockout mice (p383 MKO), but not p381 or p382 MKO, had significantly attenuated induction of PGC-11 (peroxisome proliferator receptor 3 co-activator-1) and mitochondrial enzyme expression in response to endurance exercise, and PGC-11 MKO mice phenocopied p383 MKO, indicating the importance of the p383-PGC-11 axis in muscle physiological adaptation. In cultured myotubes, we and others have shown that atrophy induced by the oxidant hydrogen peroxide could be blocked by inhibitors to p381/p382, resulting in attenuated induction of E3 ubiquitin ligases and autophagy-related genes. Together with the previous finding in cultured myotubes that knockdown of p381 attenuates saturated fatty acid-induced insulin resistance, this supports the view that p381/p382 are involved in these pathological processes in skeletal muscle. Two important issues remain to be addressed. First, the underlying mechanism for isoform-specific p38 signaling in adult skeletal muscle is unknown. Second, although we have shown a key role for p383 in exercise-induced muscle adaptation, nothing is known about the function of p38 isoforms in catabolic muscle wasting and insulin resistance. To address these issues, we propose to: 1) define isoform-specific p38 activation in skeletal muscle in vivo;2) elucidate the functional role of p383 in skeletal muscle in vivo;and 3) ascertain the role of p381/p382 in skeletal muscle dysfunction in vivo. An improved understanding of this extremely important signaling pathway will facilitate the development of new interventions for numerous medical conditions, such as cardiac cachexia and type 2 diabetes that are profoundly influenced by skeletal muscle function. PUBLIC HEALTH RELEVANCE: Previous studies implicate that the p38 mitogen-activated protein kinases in skeletal muscle may play important roles in health and disease. This study will thoroughly investigate the role of different isoforms of p38 in cachexia (severe loss of muscle mass and function) and insulin resistance (decreased sensitivity to insulin produced by pancreas). There are currently no treatments that efficiently reverse these clinically important disorders, and we predict that specific targeting of these different p38 forms will represent new inroads for effective pharmacological interventions.