Effects of a high fat diet and/or overload on striated muscle structure, function, or metabolism

Consumption of a high fat diet combined with physical inactivity is associated with many adverse health effects including obesity, insulin resistance/type 2 diabetes, and cardiovascular disease/myocardial infarction. The overall goal of this dissertation was to examine the effects of a high fat diet and/or an increase in mechanically loaded physical activity on striated muscle structure, function and/or metabolism. Resistance exercise training is beneficial for lowering hyperglycemia in type 2 diabetes. Unfortunately, the cellular and metabolic mechanisms underlying this effect are not fully understood. Thus, aim 1 was to determine whether mechanosensitive changes in glucose metabolism underlie the ability of overload to stimulate glucose uptake in insulin resistant muscle. Male mice were fed a high fat diet for 12 weeks to induce muscle insulin resistance. Plantaris muscle overload was induced by unilateral synergist ablation for 5 days. Muscle glucose metabolism was assessed using radioactive tracers and measurements of key metabolites. The results from this study indicated that overload alters the cellular fate of glucose in both healthy and insulin resistant skeletal muscle, resulting in greater glycogen content, lactate secretion, pentose phosphate and hexosamine pathway activation.Individuals with type 2 diabetes are at higher risk of experiencing myocardial infarction and having worse outcomes. EphrinA1 is a protein that binds erythropoietin-producing hepatocellular carcinoma A (EphA) receptors on the cell surface of cardiomyocytes. Importantly, previous work in hearts from healthy, chow diet fed mice demonstrated that activation of EphA/ephrinA signaling protects against myocardial ischemia/reperfusion injury. Whether activation of EphA/ephrinA signaling could be cardioprotective following ischemia/reperfusion injury in hearts from high fat diet-induced insulin resistant mice is currently unknown. Thus, aim 2 assessed whether high fat diet-induced impairments in cardiac dysfunction and morphology are associated with changes in myocardial ephrinA1/EphA expression. Male and female mice were fed a high fat diet for 12 weeks. Cardiac function was assessed by echocardiography, cardiac morphology by histology, and ephrinA1/EphA expression by immunoblot analyses. The results from this study indicated that EphA/ephrinA expression is not associated with high fat diet-induced cardiac dysfunction or altered morphology