Grant: Project Grant

Cachexia is a debilitating syndrome characterized by uncontrollable body weight loss that arises in patients with pro-inflammatory conditions, such as cancer. Numerous pathophysiological events have been associated with cachexia, including anorexia, liver dysfunction, fat tissue depletion, and, notably, loss of skeletal muscle mass. Loss of muscle mass during cachexia leads to weakness, lower quality of life, and is associated with reduce response to disease treatment. While our understanding of how cachexia is initiated is still incomplete, it is well established that chronically elevated proinflammatory hormones, also known as cytokines, are a primary driver of the condition. However, therapies against these cytokines have proven ineffective, indicating that no one inflammatory hormone is the primary driver of this syndrome. This highlights the need to identify common downstream pathways that are induced in affected tissues for targeted therapeutics. Recently, impairment of mitochondrial function and metabolic aberrations in muscle have been associated with the cachectic phenotype. However, the intra-cellular mechanisms leading to this dysfunction remain elusive. We have acquired preliminary data suggesting that elevated nitric oxide (NO) levels produced from inducible nitric oxide synthase (iNOS) during cytokine exposure is a primary cause of mitochondrial impairment in skeletal muscle. In past studies, we also showed that iNOS/NO is a key mediator of the cachectic phenotype by affecting the expression of factors, such as MyoD, which are required for muscle formation. Thus, we propose to study in this grant how NO production from iNOS alters metabolic function and the expression of factors such as MyoD in muscles exposed to cachectic stimuli, as well as the impact of these changes on muscle function. In doing so, we hope to increase our understanding of how cytokines induce atrophy and dysfunction in muscle and identify novel targets for therapeutic development.