Elucidating molecular mechanisms of muscle wasting in chronic diseases.

摘要

Skeletal muscle represents one of the most abundant tissues in our body that primarily acts as a protein reservoir as well as maintains the structural framework of the body regulating important life processes. Similar to other muscle tissues, skeletal muscle maintains its mass and functionality by balancing the rate of muscle synthesis and degradation. However, disruption of this intricate balance results in debilitating wasting conditions such as myopathies and dystrophies that not only adversely affects skeletal muscle but also promotes whole body catabolism. In several chronic diseases including cancer, sustained muscle wasting eventually culminates in respiratory failure, morbidity and increased mortality with no available therapeutic interventions.; The main goal of my research has been focused on understanding the molecular mechanisms that regulate skeletal muscle wasting in chronic disease states. In cancer mediated muscle wasting, we first utilized a morphological approach to characterize structural changes in a cachectic muscle that eventually lead us to investigate the molecular events that regulate such changes. Using murine models of cancer cachexia as well as clinical samples from cancer patients, these studies have elucidated three main molecular changes in a cachectic muscle. One of the early visible alterations involved membrane abnormalities that were accompanied by the loss and post-translational modifications in the members of a multimeric protein complex known as the dystrophin glycoprotein complex (DGC), mostly implicated in muscular dystrophies. Interestingly, contrary to the commonly accepted notion, the third event in muscle wasting was a highly selective and tightly controlled process. Among the myriad of proteins that comprise skeletal muscle, the core myofibrillar protein, myosin heavy chain was found to be a preferred target of the degradation machinery in cancer cachexia. Taken together, these studies have elucidated a hierarchy of molecular events that precede and in turn regulate muscle turnover in cancer that might be important in designing targeted therapies in the future. Primarily deregulated in response to tumor factors in cancer, DGC function is instead inactivated by mutations in the case of muscular dystrophies. DGC alterations thus served as a commonality between the two myopathies that propelled us to further investigate the molecular mechanisms that regulate muscular dystrophies. One of the signaling networks that is highly activated in muscular dystrophies, in particular, in Duchenne muscular dystrophy (DMD) is the IKK/NF-kappaB signaling pathway. To elucidate the role of the IKK/NF-kappaB signaling in the pathogenesis of DMD, we have utilized conditional mutants as well as pharmacological inhibitors of the IKK signaling pathway in mdx mice, a mouse model of DMD. Our results indicate that NF-kappaB signaling in activated macrophages functions to promote inflammation and muscle necrosis and in skeletal muscle fibers limits the regenerative capacity through the inhibition of muscle progenitor cells.