There is a critical need to understand the fundamental antioxidant properties of heat shock proteins (HSPs) in skeletal muscle and establish novel HSP therapies for preventing insulin resistance. The long-term goal is to elucidate the mechanisms of muscle insulin resistance that lead to increased prevalence of type 2 diabetes with advancing age. The objective of this particular application is to determine the extent to which increased HSP expression can modulate stress kinase and insulin signaling pathways in skeletal muscle. Our central hypothesis is that increased expression of HSP72 and HSP25 will decrease stress kinase activation and improve insulin signaling. Our rationale for the proposed research is that new strategies could be developed to modulate HSP-dependent pathways as a therapeutic approach to treat insulin resistance. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Identify HSP-dependent mechanisms that function to improve skeletal muscle insulin signaling;2) Identify signaling pathways that modulate HSP expression in insulin-resistant skeletal muscle;and 3) Identify therapeutic interventions to improve HSP activation and insulin signaling in aged skeletal muscle.
In Specific Aim 1, we will determine whether increased expression of HSP72 and HSP25 inhibit the stress kinases c-jun terminal kinase (JNK) and inhibitor of kappa B kinase 2 (IKK2), respectively, and improve insulin signaling in young (6- and 12-month-old) and aged (18- and 24-month-old) Fischer 344 rats. We will use both heat treatment and specific overexpression of HSPs via plasmid transfection to accomplish this aim.
In Specific Aim 2, we will determine the extent to which glycogen synthase kinase-3 (GSK-3) and JNK signaling pathways modulate HSP expression in insulin-resistant skeletal muscle. Pharmacolgocial inhibitors of GSK-3 and JNK will be used to modify activation of the primary HSP transcription factor, heat shock factor 1 (HSF-1).
In Specific Aim 3, we will examine the ability of exercise training to increase the HSP response in young and aged, insulin-resistant skeletal muscle. Our working hypothesis is that exercise training will trigger the HSP response through a pathway independent of heat treatment, and that heat stress and exercise will result in an additive improvement of insulin signaling and glucose uptake in aged, insulin-resistant skeletal muscle. As an outcome of the proposed aims, we expect to establish a novel therapeutic role for HSPs in combating insulin resistance and identify molecular mechanisms that regulate HSP expression in aged, insulin-resistant skeletal muscle. This project is innovative, because it is designed to identify a previously unexplored mechanism for improving insulin resistance via increased expression of HSPs in skeletal muscle. The proposed research is significant because it will help to establish important new candidate targets for prevention of insulin resistance as well as enhance our understanding of the decline in cellular defenses that occurs with age and disease.
At the completion of these studies, we expect to increase our understanding of the fundamental antioxidant properties of heat shock proteins in skeletal muscle and to identify the heat shock protein-dependent mechanisms underlying the protective effect of heat treatment on insulin action. Such results would have an important positive impact on public health by identifying new targets for therapeutic interventions that will aid the growing number of elderly persons in the U.S. at risk for developing insulin resistance and type 2 diabetes.
|Rogers, Robert S; Morris, E Matthew; Wheatley, Joshua L et al. (2016) Deficiency in the Heat Stress Response Could Underlie Susceptibility to Metabolic Disease. Diabetes :|
|Rogers, Robert S; Beaudoin, Marie-Soleil; Wheatley, Joshua L et al. (2015) Heat shock proteins: in vivo heat treatments reveal adipose tissue depot-specific effects. J Appl Physiol (1985) 118:98-106|
|Smittkamp, Susan E; Morris, Jill K; Bomhoff, Gregory L et al. (2014) SOD1-G93A mice exhibit muscle-fiber-type-specific decreases in glucose uptake in the absence of whole-body changes in metabolism. Neurodegener Dis 13:29-37|
|Grote, Caleb W; Groover, Anna L; Ryals, Janelle M et al. (2013) Peripheral nervous system insulin resistance in ob/ob mice. Acta Neuropathol Commun 1:15|
|Touchberry, Chad D; Gupte, Anisha A; Bomhoff, Gregory L et al. (2012) Acute heat stress prior to downhill running may enhance skeletal muscle remodeling. Cell Stress Chaperones 17:693-705|
|Spangenburg, Espen E; Geiger, Paige C; Leinwand, Leslie A et al. (2012) Regulation of physiological and metabolic function of muscle by female sex steroids. Med Sci Sports Exerc 44:1653-62|
|Gorres, Brittany K; Bomhoff, Gregory L; Gupte, Anisha A et al. (2011) Altered estrogen receptor expression in skeletal muscle and adipose tissue of female rats fed a high-fat diet. J Appl Physiol 110:1046-53|
|Morris, J K; Seim, N B; Bomhoff, G L et al. (2011) Effects of unilateral nigrostriatal dopamine depletion on peripheral glucose tolerance and insulin signaling in middle aged rats. Neurosci Lett 504:219-22|
|Morris, J K; Bomhoff, G L; Gorres, B K et al. (2011) Insulin resistance impairs nigrostriatal dopamine function. Exp Neurol 231:171-80|
|Grote, C W; Morris, J K; Ryals, J M et al. (2011) Insulin receptor substrate 2 expression and involvement in neuronal insulin resistance in diabetic neuropathy. Exp Diabetes Res 2011:212571|
Showing the most recent 10 out of 14 publications