| dc.description.abstract | The lack of physical activity with or without advancing age is often accompanied by a dysregulation of skeletal muscle metabolism, leading to impaired muscle function and disease. While causes of skeletal muscle dysfunction are numerous, it is understood that the preservation/restoration of normal skeletal muscle metabolism is a consistent factor involved in the prevention, development, and progression of many of these conditions. An emerging candidate for the control of metabolic disease is Ghrelin, a multi-isoform peptide hormone that has been suggested both as a culprit and a potential therapeutic target because of its impact on inflammation and glucose uptake, both hallmarks of muscle dysfunction. Despite its documented role in the body, very little is known about ghrelin’s direct impact on skeletal muscle. The purpose of this dissertation was to assess the direct action of ghrelin and its receptor on metabolic and anabolic signaling in skeletal muscle. We hypothesized that the role of ghrelin in the control of metabolic disease was via a direct action on skeletal muscle, a major site for glucose disposal, but our findings indicate that ghrelin-mediated actions are primarily on other tissues that subsequently influence skeletal muscle. Using healthy, cultured myotubes and genetically altered mice that did not express the ghrelin receptor, we assessed the direct action of both isoforms of ghrelin on mechanisms of insulin-dependent and independent skeletal muscle glucose uptake. Our results demonstrated, in culture, that the two isoforms do have unique actions in skeletal muscle and confirm that AG negatively impacts glucose uptake, potentially through upregulation of 4E-BP1. Further, our data indicate that the positive influence attributed to UAG for glucose uptake is due to insulin-independent actions via AMPK but the overall response is less convincing than previous work. Global knock-out of the ghrelin receptor, GHS-R1a, in mice mitigated the metabolic dysregulation observed with advanced age. The present outcomes indicate that whole-body disruptions of glucose regulation, in part, are mediated by the presence of the acylated isoform of ghrelin, but the purported
‘improvements’ from unacylated ghrelin through a direct interaction in skeletal muscle may be overstated. | |
