This proposal describes a 5 year project which will facilitate my career goals to become an independent investigator. I put forth a training and career development plan which includes a research proposal with strong implications on the understanding of muscle physiology and human disease, training in laboratory techniques, and fundamental seminars to aide in research strategy and career development. I will be mentored by Dr. C. Ronald Kahn, a world leader in the field of insulin signaling, who has trained greater than 160 scientists many of whom are leaders in their field. Additionally, I have assembled an excellent committee for scientific and career advice. I will train at Joslin Diabetes Center, an affiliate of Harvard, an epicenter of excellent research. The goal of my project is to understand the role of IGF-1 and insulin signaling in muscle protein metabolism and mitochondrial function. Muscle insulin resistance and mitochondrial dysfunction are hallmarks of type 2 diabetes, but also occur in uncontrolled type 1 diabetes and critical illness. Muscle atrophy associated with these conditions is detrimental to health. Signaling via the insulin receptor (IR) and the closely related IGF-1 receptor (IGFR) enhances protein synthesis and inhibits degradation, yet the relative contribution and mechanisms by which insulin or IGF-1 signaling inhibits muscle atrophy or alters mitochondrial function under normal and diabetic conditions have not been fully elucidated. My preliminary data show that loss of both IR and IGFR in muscle dramatically decreases muscle size, increases markers of autophagy, and impairs muscle function in the absence of altered glucose homeostasis.
Aim 1 will decipher the relative roles of IR or IGFR signaling on muscle protein metabolism and autophagy.
Aim 2 will discover the downstream targets of IR/IGFR signaling that mediate the alterations in protein turnover and autophagocytic flux in response to diabetes and muscle insulin resistance.
Aim 3 will determine the role of altered IR and IGFR signaling on muscle mitochondrial function and autophagocytic clearance of mitochondria, or """"""""mitophagy"""""""". This study will elucidate the roles of insulin resistance, altered IGF-1 signaling and diabetes on muscle protein metabolism and hopefully identify therapeutic targets to both decrease muscle atrophy and enhance mitochondrial function.
Uncontrolled diabetes and insulin-resistant states are associated with muscular dysfunction and even muscular atrophy, which can have a significant impact on health. We discovered that complete lack of signaling by insulin and the closely related hormone insulin-like growth factor-1 (IGF-1) in skeletal muscle leads to marked muscular atrophy and an activation of the autophagy-lysosome pathway, which degrades muscle protein and induces mitochondrial breakdown (i.e. mitophagy). This proposal will determine how insulin and IGF-1 control autophagy and mitophagy in skeletal muscle to provide a better understanding of the muscular abnormalities that occur with diabetes and insulin resistance.
|James, Haleigh A; O'Neill, Brian T; Nair, K Sreekumaran (2017) Insulin Regulation of Proteostasis and Clinical Implications. Cell Metab 26:310-323|
|Cai, Weikang; Sakaguchi, Masaji; Kleinridders, Andre et al. (2017) Domain-dependent effects of insulin and IGF-1 receptors on signalling and gene expression. Nat Commun 8:14892|
|Sakaguchi, Masaji; Fujisaka, Shiho; Cai, Weikang et al. (2017) Adipocyte Dynamics and Reversible Metabolic Syndrome in Mice with an Inducible Adipocyte-Specific Deletion of the Insulin Receptor. Cell Metab 25:448-462|
|Boucher, Jeremie; Softic, Samir; El Ouaamari, Abdelfattah et al. (2016) Differential Roles of Insulin and IGF-1 Receptors in Adipose Tissue Development and Function. Diabetes 65:2201-13|
|O'Neill, Brian T; Lee, Kevin Y; Klaus, Katherine et al. (2016) Insulin and IGF-1 receptors regulate FoxO-mediated signaling in muscle proteostasis. J Clin Invest 126:3433-46|
|O'Neill, Brian T; Segkos, Konstantinos; Kasper, Ekkehard M et al. (2016) Non-metastatic squamous cell carcinoma within a Rathke's cleft cyst. Pituitary 19:105-9|
|Wang, Xuanchun; Lockhart, Samuel M; Rathjen, Thomas et al. (2016) Insulin Downregulates the Transcriptional Coregulator CITED2, an Inhibitor of Proangiogenic Function in Endothelial Cells. Diabetes 65:3680-3690|
|Li, Mengyao; Vienberg, Sara G; Bezy, Olivier et al. (2015) Role of PKC? in Insulin Sensitivity and Skeletal Muscle Metabolism. Diabetes 64:4023-32|
|O'Neill, Brian T; Lauritzen, Hans P M M; Hirshman, Michael F et al. (2015) Differential Role of Insulin/IGF-1 Receptor Signaling in Muscle Growth and Glucose Homeostasis. Cell Rep 11:1220-35|
|Roberts-Toler, Carla; O'Neill, Brian T; Cypess, Aaron M (2015) Diet-induced obesity causes insulin resistance in mouse brown adipose tissue. Obesity (Silver Spring) 23:1765-70|