Date of Award
Doctor of Philosophy (PhD)
Thomas J Hawke
Type 1 diabetes mellitus (T1DM) is a disease defined by its complications as much as its central pathology. One such complication, diabetic myopathy, has received more attention in recent years as it has become clear that by maintaining a healthy skeletal muscle mass, diabetic individuals are more likely to maintain metabolic control and avoid the health consequences associated with hyperglycemia. While only a limited number of studies have been performed on diabetic human skeletal muscle, the research clearly indicates that a loss of muscular strength and alterations in muscle phenotype are a result of T1DM, occurring within weeks of disease inception. Studies employing rodent models of T1DM have identified several key changes underlying the loss of contractile capacity and the changes to muscle phenotype. The research to date, however, has yet to thoroughly elucidate the mechanisms underlying diabetic myopathy. The goal of the following studies is to gain a more thorough understanding of the effects of T1DM on skeletal muscle contractile capacity, morphology, and regenerative capacity using the C57BL/6J-Ins2Akita (Ins2WT/C96Y) diabetic mouse model. Given the crucial role of muscle repair in maintaining a healthy muscle mass, any deficit observed here could have important implications in the pathophysiology of diabetic myopathy. The results of the following studies indicate that the Ins2WT/C96Y mouse undergoes a loss of glycolytic muscle mass and other morphological/phenotypic alterations concomitant with loss of peak contractile force. Furthermore, the regenerative capacity of the muscle following injury is impaired in glycolytic muscle groups, particularly the tibialis anterior (TA). This impairment in regeneration can be, at least partly, attributed to chronic elevation in plasminogen activator inhibitor-1 (PAI-1). Pharmacological inhibition of this hormone improves regeneration of the TA in the Ins2WT/C96Y mouse. These data have improved our mechanistic understanding of diabetic myopathy and have clinical implications for the treatment of T1DM.
Krause, Matthew P., "DIABETIC MYOPATHY: CHANGES TO CONTRACTILE FUNCTION, MORPHOLOGY AND REGENERATIVE CAPACITY OF SKELETAL MUSCLE IN A MURINE MODEL OF TYPE 1 DIABETES MELLITUS" (2011). Open Access Dissertations and Theses. Paper 6196.
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