Muscle-bone Interaction and its Role in Diabetic Bone Disease of Type I Diabetes

Summary The bone fracture incidence observed in individuals with Type 1 diabetes (T1D) is much higher compared to the general population. The burden of diabetic bone disease is partially due to lack of evidence to support targeted prevention and interventions to reduce fractures in this population. Furthermore, those with T1D exhibit skeletal muscle dysfunction associated with decreased muscle strength and muscle mass. Skeletal muscle and bone communication is a potential modifiable factor that could contribute to the development of diabetic musculoskeletal disease. More specifically, the candidate proposes that a myokine called myostatin, is directly involved in the development of diabetic bone disease and could associate with skeletal muscle dysfunction. The role of myostatin in T1D and how it affects the musculoskeletal system in this disease are questions that will be addressed with this proposal. Specifically, the three aims of this proposal are: 1. Quantify the relationship between myostatin levels in serum and skeletal muscle, and bone parameters of humans with and without T1D; 2A. Quantify the relationship between myostatin levels in serum and muscle and the bone phenotype of mice with insulin-deficient diabetes; 2B. Evaluate whether inhibition of myostatin is beneficial for the prevention of DBD in insulin-deficient diabetes; and lastly 3: Determine the mechanism of action of myostatin on osteoblastic bone cells under hyperglycemic conditions. Myostatin, which is believed to negatively affect both bone and skeletal muscle, could serve both as a marker of musculoskeletal function and surrogate for risk for fracture in those with T1D. Additionally, it may offer an opportunity for targeted intervention to prevent or improve musculoskeletal dysfunction associated with T1D. The knowledge gained from these studies will set the ground for future studies in musculoskeletal health in diabetes and will offer the candidate with an opportunity to transition towards an independent career in the abovementioned field. This proposal presents a five-year research career development program focused on the study of muscle and bone interactions in Type 1 diabetes; and specifically, how muscle derived molecules, called myokines contribute to diabetic bone disease, a serious and emerging complication of Type 1 diabetes. The candidate currently holds a position as an Assistant Professor of Pediatrics in the Division of Pediatric Endocrinology at the University of Kentucky. She has 75% protected time for research, independent office space, laboratory space and access to all equipment and resources offered by the Barnstable Brown Diabetes Center. The candidate is strongly committed to an academic career in the field of musculoskeletal research in diabetes and is supported by her mentors and her department. The proposed study and the complementary didactic work will provide the candidate with research skills in basic, translational and clinical research thereby enabling to transition to independence as a clinician scientist.