Myokines Involved in the TGF-Activing Signaling Pathway in Type 1 diabetes

Summary 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 may contribute to development of diabetic musculoskeletal disease. More specifically, the candidate proposes that myokine secretion from skeletal muscle is dysregulated and may be involved in development of diabetic bone disease and associate with skeletal muscle dysfunction. The role of myokines that belong to a signaling pathway, the TGF- β/activin/myostatin pathway in T1D and how it affects the musculoskeletal system in this disease are gaps in knowledge that will be addressed with this proposal. Specifically, the two aims of this proposal are: 1. Determine gene expression of members of the TGF-β /myostatin/activin pathway in skeletal muscle in humans with T1D and myokines produced by muscle progenitor cells (MPCs) in vitro after differentiation into myotubes. 2. Focus on members of the TGF-β /myostatin/activin pathway identified as dysregulated in SA 1 and examine them in mice with and without insulin-deficient diabetes. Subaim 2a: Quantify their gene expression in skeletal muscle and in myotubes (including their secretion in conditioned media) from mice, and Subaim 2b: Quantify them in osteoblasts from mice to determine whether their levels are altered with insulin-deficient diabetes. Myokines involved in this pathway 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. This proposal presents a one year research project focused on the study of muscle and bone interactions in T1D; and specifically, how muscle derived molecules, called myokines are differentially secreted in T1D. The candidate currently holds a position as an Assistant Professor of Pediatrics in the Division of Pediatric Endocrinology at the University of Kentucky and is strongly committed to an academic career in the field of musculoskeletal research in diabetes The proposed study will provide the candidate with preliminary data to apply for extramural funds (R01).