Document Details

Document Type:   Dissertation
Title:   Muscle Plasticity and Intramuscular Signaling in the Insulin-Resistant Obese Zucker Rat
Author:   Anjaiah Katta
College:   Joan C. Edwards School of Medicine
Degree Program:   Biomedical Sciences, Ph.D.
Degree:   Doctor of Philosophy
Committee Director:   Eric R. Blough
Document Availability:   Document available for World-Wide access.
Date of Defense:   August 2011

The ability to increase skeletal muscle mass may have important implications for the treatment of insulin resistance (IR) and diabetes [1-3]. Recent data suggest that IR muscle may adapt differently than normal muscle; however, molecular mechanism(s) responsible for this finding are not well understood [4]. Herein, we investigate the molecular mechanisms underlying the skeletal muscle remodeling in the IR Obese Zucker (OZ) rat. The OZ rat is characterized by skeletal muscle insulin resistance, hyperglycemia, and hyperlipidemia. Compared to LZ rats, our data demonstrate that soleus muscle hypertrophy was significantly attenuated in the OZ rats after 3-weeks of muscle overload and that these findings appear to be accompanied by significant impairments in the ability of the soleus to undergo. phosphorylation of mammalian target of rapamycin (mTOR), 70 kDa ribosomal protein S6 kinase (p70S6k), ribosomal protein S6 (rpS6) and protein kinase B (Akt) Recent in vitro and in vivo studies have suggested a role for AMP-activated protein kinase (AMPK) and dsRNA-dependent protein kinase (PKR) in skeletal muscle adaptation and their interactions with mTOR related signaling [5, 6]. Our data suggest that IR attenuates overload-induced skeletal muscle hypertrophy through the activation of AMPK and PKR, which appears to be associated with an inhibition of mTOR and eIF2α phosphorylation. This finding is consistent with the possible depression of protein synthesis. Other data demonstrate that IR resistance is associated with the PKR-mediated activation of p38 MAP kinase, which would be predicted to lead to increased protein degradation. Further, we demonstrated that the regulation of heat shock proteins (HSPs) and the mitogen-activated protein kinases (MAPKs) are altered during hypertrophy in OZ rat, which suggest that these molecules may play a role in explaining why IR may be associated with alterations in muscle plasticity. In addition to traditional biochemical signaling cascades, recent data have strongly suggested that muscle-specific miRNAs may participate in the regulation of load-induced skeletal muscle remodeling [7]. To this end, we demonstrate for the first time that miR-1 and miR133 expression levels are lower in IR muscle. Further, we also observed that overload decreased mir-1 expression in the LZ muscle to a greater extent to that measured in the OZ muscle. Combined, these results are the first to report evidence that overload-induced skeletal muscle remodeling in IR OZ rat is associated with multiple level decrements including changes in mTOR signaling, hyperphosphorylation of AMPK and PKR and altered regulation of muscle-specific miRNAs. 

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