Skeletal muscle dysfunction contributes significantly to the many sequelae of Type 2 Diabetes (T2D). Although the majority of mechanistic studies directed towards describing diabetic skeletal muscle dysfunction focus on a single cell type, it is more prudent to investigate the mechanistic interaction linking different types of cells. For example, the maintenance of skeletal muscle homeostasis in vivo is a coordinated interaction between the myogenic cells and the vasculature. Satellite cells from myopathic muscle have been shown to have a diminished effect on angiogenesis, so it is reasonable to speculate that satellite cells from diabetic muscle also have a weakened ability to maintain vessel function. An understanding of the coordinated interaction between satellite cells and the vasculature requires an understanding of the mechanisms that regulate satellite cell-mediated effects on angiogenesis. The overall objective of this application is to elucidate the satellite-cell mediated mechanisms that contribute to diabetic skeletal muscle dysfunction. The central hypothesis is that satellite cells derived from diabetic muscle exhibit changes in their exosomes that are manifested as an impaired ability to promote angiogenesis. The completion of the overall objective for this project will be accomplished by pursuing three specific aims: (1) Identify the satellite cell-dependent mechanisms that contribute to impaired angiogenesis in diabetic muscle; (2) Elucidate the role of SIRT1 in mediating satellite cell-dependent mechanisms in diabetic muscle; and, (3) Determine the mechanisms that cause diminished satellite cell-dependent activity in diabetic muscle after ischemia-reperfusion (I/R) injury. The outcome of these three separate, but related, specific aims will be the determination of the mechanisms that control the ability of satellite cells to affect angiogenesis in diabetic muscle, including during repair after injury.

Public Health Relevance

Skeletal muscle dysfunction is a major contributor to the negative consequences of Type 2 diabetes. The mechanisms that are responsible for the coordinated interaction between myogenic cells and vascular cells in diabetic skeletal muscle are not understood. The goal of this project is to gain insight into the mechanisms that affect the ability of satellite cells (stem cells resident in muscle) to influence vessel growth in diabetic muscle to enable a more effective development of therapies to treat it.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Enhancement Award (SC1)
Project #
5SC1DK122578-02
Application #
9876948
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Agodoa, Lawrence Y
Project Start
2019-03-01
Project End
2023-02-28
Budget Start
2020-03-01
Budget End
2021-02-28
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
800189185
City
San Antonio
State
TX
Country
United States
Zip Code
78249