Skeletal muscle atrophy is the most common clinical disorder of skeletal muscle and typically occurs as a secondary consequence of fasting, disuse, acute and chronic illness, and aging. It can lead to prolonged recovery and loss of independent living. Of similar clinical significance, one third of Americans are obese and at risk for metabolic syndrome. Interestingly recent studies have demonstrated that both metabolic syndrome and obesity diminish skeletal muscle strength, power, and endurance. However, there are no effective pharmacological treatments for these debilitating effects on skeletal muscle. This is largely due to the fact that the molecular mechanisms underlying its pathogenesis remain uncharacterized. We have recently identified ursolic acid (UA) as a small molecule inhibitor of muscle atrophy. In the absence of atrophy-inducing stress, UA-supplemented chow elicited muscle hypertrophy with little adiposity in mice. To further evaluate these data, mice were subjected to a high fat diet (HFD) with or without UA supplementation, or a standard chow (SC) control. Our data indicates that UA-supplemented HFD mitigates muscle atrophy and adiposity, while HFD significantly reduces muscle mass compared to SC. Furthermore, mice fed a HFD exhibited increased adiposity and reduced muscle mass, strength, and fiber diameter when compared to SC controls. Molecular analysis revealed diminished protein content and increased triglycerides. Gene expression analysis revealed a reduction in Pgc1&agr;, a critical gene that regulates oxidative metabolism and mitochondrial biogenesis. Additionally, we found decreased expression of hormonal receptors AR, involved in signaling of testosterone, and Thr&agr;, involved in signaling of thyroid hormones. Taken together, these data suggest that alterations in gene expression resulting from diet-induced obesity are an atrophy-inducing stress that may function by disrupting metabolic and hormonal signaling.
|Advisor:||Adams, Christopher M.|
|Commitee:||Benson, Christopher, Motto, David|
|School:||The University of Iowa|
|School Location:||United States -- Iowa|
|Source:||MAI 51/02M(E), Masters Abstracts International|
|Subjects:||Molecular biology, Cellular biology|
|Keywords:||Atrophy, Obesity, Skeletal muscle|
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