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.
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.
|Call, Jarrod A; Chain, Kristopher H; Martin, Kyle S et al. (2015) Enhanced skeletal muscle expression of extracellular superoxide dismutase mitigates streptozotocin-induced diabetic cardiomyopathy by reducing oxidative stress and aberrant cell signaling. Circ Heart Fail 8:188-97|
|Cohen, Todd J; Choi, Moon-Chang; Kapur, Meghan et al. (2015) HDAC4 regulates muscle fiber type-specific gene expression programs. Mol Cells 38:343-8|
|Chao, Hongxia; Li, Haochen; Grande, Rebecca et al. (2015) Involvement of mTOR in Type 2 CRF Receptor Inhibition of Insulin Signaling in Muscle Cells. Mol Endocrinol 29:831-41|
|Lee, Hui-Young; Gattu, Arijeet K; Camporez, JoÃ£o-Paulo G et al. (2014) Muscle-specific activation of Ca(2+)/calmodulin-dependent protein kinase IV increases whole-body insulin action in mice. Diabetologia 57:1232-41|
|Hindi, Sajedah M; Mishra, Vivek; Bhatnagar, Shephali et al. (2014) Regulatory circuitry of TWEAK-Fn14 system and PGC-1* in skeletal muscle atrophy program. FASEB J 28:1398-411|
|Kenwood, Brandon M; Weaver, Janelle L; Bajwa, Amandeep et al. (2014) Identification of a novel mitochondrial uncoupler that does not depolarize the plasma membrane. Mol Metab 3:114-23|
|Laker, Rhianna C; Xu, Peng; Ryall, Karen A et al. (2014) A novel MitoTimer reporter gene for mitochondrial content, structure, stress, and damage in vivo. J Biol Chem 289:12005-15|
|Katwal, A B; Konkalmatt, P R; Piras, B A et al. (2013) Adeno-associated virus serotype 9 efficiently targets ischemic skeletal muscle following systemic delivery. Gene Ther 20:930-8|
|Meng, Zhuo-Xian; Li, Siming; Wang, Lin et al. (2013) Baf60c drives glycolytic metabolism in the muscle and improves systemic glucose homeostasis through Deptor-mediated Akt activation. Nat Med 19:640-5|
|Zhang, Chenhong; Li, Shoufeng; Yang, Liu et al. (2013) Structural modulation of gut microbiota in life-long calorie-restricted mice. Nat Commun 4:2163|
Showing the most recent 10 out of 33 publications