Muscular dystrophies are inherited, progressive muscle disorders that result in severe muscle weakness, cardiomyopathy, loss of ambulation and early death. Cardiomyopathy is the cause of death in 20-30% of patients. More than 30 different genes cause muscular dystrophy with some of the most common gene mutations affecting the expression or function of the proteins of the dystrophin glycoprotein complex (DGC). Like many genetic diseases, the resulting disease phenotypes represent a combination of direct effects of the primary gene mutation on muscle and the heart, and secondary phenotypes and environmental influences that impact overall muscle and heart function. While environmental influences such as exercise are beneficial for muscle and hearts of healthy individuals, because both skeletal and cardiac muscles in dystrophic animals are sensitive to muscle injury, the impact of exercise on disease outcome and recommendations for activity in dystrophic patients are not clear. Our understanding of the mechanisms of muscular dystrophy, and many other genetic and acquired diseases, has grown considerably due to the availability of targeted mouse strains that recapitulate many important aspects of disease. State of the art approaches to study cardiovascular function in mice now rival many of the imaging and invasive catheterization methods that can be performed in humans. A mentoring portion of this proposal is to mentor the next generation of investigators in state of the art comprehensive cardiovascular phenotyping though development and execution of a series of modular, hands-on short courses and workshops to train fellows, graduate students and independent scientists. The research project portion of this proposal will take advantage state of the art radiotelemetry and cardiac phenotyping approaches to 1) genetically dissect the interplay between direct effects of loss of DGC function on the heart and the hypothesized dysfunction of the peripheral vasculature in dystrophic skeletal muscle on overall cardiovascular function and 2) Determine the molecular and physiological mechanisms of how acute and chronic exercise impact the progressive development of cardiomyopathy in dystrophic animals.

Public Health Relevance

The proposed research will provide mentored training to the next generation of scientists in state of the art, comprehensive murine cardiovascular phenotyping. Genetic approaches in mice, combined with physiological phenotyping, will be aimed at dissecting the important role of exercise and skeletal muscle dysfunction on overall cardiovascular health and cardiomyopathy progression in muscular dystrophy.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
Midcareer Investigator Award in Biomedical and Behavioral Research (K26)
Project #
1K26OD016502-01
Application #
8487847
Study Section
Special Emphasis Panel (ZTR1-CM-6 (01))
Program Officer
Mirochnitchenko, Oleg
Project Start
2013-06-15
Project End
2018-03-31
Budget Start
2013-06-15
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$78,270
Indirect Cost
$5,798
Name
University of Michigan Ann Arbor
Department
Physiology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Reifler, Aaron; Li, Xingli; Archambeau, Ashley J et al. (2014) Conditional knockout of pik3c3 causes a murine muscular dystrophy. Am J Pathol 184:1819-30