Manipulating skeletal muscle buffers cardiometabolic dysfunction in disease

Diabetes mellitus is a worldwide epidemic that burdens over 500 million people globally and was responsible for 6.7 million deaths in 2021. Unfortunately, the incidence of diabetes is increasing and surpassing past predicted rates: presently researchers forecast a diabetic caseload of 1.05 billion by the year 2045. Veterinary medicine is also experiencing an increase in diabetic caseloads in companion animals. Diabetes is defined as a state of dysfunctional glucose handling resulting in chronic hyperglycemia. This disease is further characterized as Type 1 and Type 2 with both types resulting in chronically elevated blood glucose levels due to inadequate insulin production. Hyperglycemia has many detrimental effects to an individual, such as vasculitis, hypertension, nephropathy, neuropathy, skeletal muscle mass and function loss, and other metabolic disturbances. Importantly, the most beneficial non-pharmacological intervention for diabetes management is exercise. As the largest glucose sink in the body, an individual’s skeletal muscle mass heavily influences their glucose metabolism and overall health parameters. Unfortunately, diabetes itself causes skeletal muscle mass loss and weakness, reducing the overall benefits of what skeletal muscle could provide. Skeletal muscle contains oxidative and glycolytic fibers; however, it is unknown which fiber type is more advantageous in each type of diabetes. To investigate these questions, we utilized two novel mouse models for each type: an increased glycolytic skeletal muscle phenotype through myostatin deletion for Type 1 Diabetes and an increased oxidative skeletal muscle phenotype through Peroxisome proliferator-activated receptor Gamma Coactivator-1 alpha (PGC-1α) overexpression for Type 2 Diabetes. In both study models, multiple variables were assessed including glucose homeostasis via plasma glucose, HbA1c, and IGTT, fluid dynamics, skeletal muscle function, and vascular function. In both models, the improvement of skeletal muscle health improved glucose homeostasis, decreased muscle fatigability, conserved fluid dynamics, improved renal function, and restored blood glucose levels to a normal physiological state. Taken together, this data suggests that augmenting skeletal muscle is an effective treatment strategy for the cardiometabolic and muscular dysfunction that occurs with diabetes.