PGC1a overexpression protects against cardio-metabolic disease and skeletal muscle dysfunction in type 2 diabetic mouse model

Abstract

Diabetes currently afflicts 34.2 million Americans, and approximately 1 in 3 are prediabetic (CDC, 2020). Type 2 diabetes (T2D) is a metabolic disorder characterized by hyperglycemia due to the combination of insulin resistance and insufficient insulin production. Unfortunately, the reoccurring hyperglycemia in association with long-term insulin malfunction has been tied to damage or failure of differing organs such as kidney, nerves, and vasculature (American Diabetes Association, 2007). The renal dysfunction caused by the hyperglycemia is the causative agent of two prominent clinical signs of T2D, polydipsia and polyuria. The most substantial predispositions for T2D are obesity, poor nutrition, sedentary lifestyle, and aging, which all negatively effects an individual's skeletal muscle mass as well. Skeletal muscle is considered the largest metabolic reservoir due to its role as a glucose sink. Skeletal muscle can be categorized into oxidative and glycolytic fibers; however, oxidative fibers are more insulin sensitive and resistant to fatigue. Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1a) is an endogenous protein and potent activator of multiple metabolic pathways: including mitochondrial biogenesis, liver gluconeogenesis, oxidative muscle fibers, and blood glucose absorption and handling. Overexpression of PGC1a is known to increase insulin-sensitive oxidative muscle fibers but what remains unknown is whether it is effective at preventing cardiometabolic disease and skeletal muscle dysfunction in a mouse model of T2D. Our hypothesis is that overexpression of PGC1a will improve muscle performance by preventing fatigability, will preserve glucose homeostasis, and protect against kidney function in a mouse model of T2D.

The T2D mouse model utilized was the db/db mouse, which possesses a dysfunctional leptin receptor and thus is chronically hyperphagic. By 12 weeks of age, it is well characterized as a model of Type 2 diabetes. Overexpression of PGC1? was obtained by crossing the MCK-PGC1alpha transgenic mice onto the db/db background. Adult mice were used for the duration of the experiments with a total of four mouse groups; a lean control, a lean PGC1a overexpression, an obese control, and an obese PGC1a overexpression mouse. Multiple variables were assessed including glucose homeostasis (plasma glucose, HbA1c, IGTT), muscle function (in vivo plantarflexion of gastrocnemius muscle), and fluid dynamics (via metabolic cages).

Overexpression of PGC1a improves glucose homeostasis, decreases muscle fatigability, and conserves fluid dynamics in a T2D mouse model. Furthermore, the overexpression of PGC1a returns the blood glucose levels and renal function in the T2D models back to levels of the controls, restoring them to a normal physiological state. Muscle rate of fatigue was significantly decreased in both the lean and obese mice, providing superior performance against fatigability. Altogether, this data suggests that targeting PGC1a is a possible intervention for T2D and potentially other metabolic diseases.