Role of skeletal muscle mitochondrial degeneration in the development of muscle wasting
At its simplest, muscle wasting is due to an imbalance of muscle protein turnover where we break down proteins faster and we make proteins. This results in reduced muscle mass and ultimately function. However, the processes that occur leading to muscle wasting and the instigating events that cause it differ greatly between different forms of muscle wasting. Common differences in muscle wasting disorders include diverging effects on different muscle fiber types (Type 1 vs. Type 2), and how muscle protein imbalance occurs. For example, the obese Zucker rat, , has muscle wasting associated with morbid obesity – however the animal has greater basal protein synthesis compared to healthy animals, suggesting high protein break down is responsible for muscle loss in this condition.
In our laboratory we have found evidence of impaired mitochondrial quality control markers in cancer-cachexia, disuse muscle atrophy, and morbid obesity. Data in cancer-cachexia suggests these mitochondrial damages could occur before development of muscle wasting. Therefore, we recently examined mitochondrial health across the development of cancer-cachexia and found early deteriorations in mitochondrial health with the development of cancer-induced muscle wasting (Brown et al.) Mitochondrial degeneration precedes the development of muscle atrophy in progression of cancer cachexia in tumour‐bearing mice
Therefore, current experiments in our laboratory are focused on determining:
- If mitochondrial degeneration is a common precursor to muscle wasting using models of disuse atrophy in addition to our data on cancer cachexia
- What factors may induce mitochondrial degeneration during muscle wasting
- If promotion of mitochondrial health may alleviate or prevent muscle wasting across multiple forms
- If we can use data from the development of muscle wasting to guide exercise and pharmacological approaches to development of muscle wasting
Role of microRNA-16 in development of skeletal muscle insulin resistance
Insulin resistance, an inability to draw sugar from the blood into tissues and a precursor to Type 2 Diabetes Mellitus (T2DM), commonly begins at the skeletal muscle. Unfortunately, thus far, efforts to increase sugar uptake from the blood have not been effective at treating insulin resistance and preventing onset of T2DM. This is perhaps because insulin has many effects in the body, including: protein and fat synthesis as well as others. Therefore, processes other than sugar uptake may be important contributors to the development of T2DM. Recent work from our laboratory shows that small signaling factors called micro-RNAs, specifically miR-16 is downregulated in muscle of obese rats and mice as well as in muscle cells that are undergo “simulated obesity”. Additionally, miR-16 appears to control other aspects of cell function in muscle cells (Abstract: microRNA‐16 Is Downregulated During Insulin Resistance and Controls Skeletal Muscle Protein Accretion). Therefore, we are currently using cell and animal models to determine how miR-16 affects muscle physiology and the development of insulin resistance.
Autophagy work by doctoral candidate Megan Rosa-Caldwell
Autophagy is a cellular mechanism to recycle damaged or old proteins, helping to maintain cell health. However, if autophagy slows down too much, dysfunctional proteins and organelles can accumulate in the cell, causing a pile up of cellular “junk”. Exercise is generally thought to increase autophagy and contribute to healthier cells. We have recently found that the rate of autophagy in the muscle correlates to glucose tolerance in exercised mice. (Hyperlink to paper pending) However, what type of exercise contributes to increases in autophagy and if autophagy directly causes changes in glucose tolerance is still unknown. Therefore, we are comparing the effects of high intensity v. moderate intensity exercise in obese mice to see if different exercise intensities affect autophagy activation. Additionally, so see if autophagy is necessary for improving glucose tolerance during obesity, we are blocking autophagy in exercised mice to see if mice experience different adaptations compared to control mice.