Loss of mobility arising from loss of skeletal muscle function is an inevitable consequence of aging, resulting in a reduction of quality of life and increased morbidity requiring hospitalization or home care significantly raising health care costs. Severe loss of muscle function, termed sarcopenia is estimated to cost xxx as our general population ages. Sarcopenia is associated with muscle atrophy, changes in myosin isotypes, a reduction in contractile force and a diminishment in the speed of contraction. These complex physiological changes are well documented but the mechanisms responsible for these changes are not understood. A loss of regenerative capacity is generally acknowledged to accompany skeletal muscle atrophy. The cells generally acknowledged to be responsible for muscle repair are satellite cells, so named for their anatomical location between the plasma membrane of the skeletal muscle myofiber and the basement membrane. Predominately mitotically quiescent, these cells can be activated, will proliferate and differentiate to either maintain or repair skeletal muscle. Although satellite cells isolated from aged and young muscles appear to differ in their behavior, it is not clear whether the observed differences are intrinsic or simply a different response to the stresses of cell culture. Conflicting reports debate on whether satellite cell numbers decrease or remain unchanged as skeletal muscle ages. How satellite cell numbers are maintained is not known. Several groups including our own have identified subsets of satellite cells that behave as stem cells, capable of renewing the satellite cell pool and commitment to myogenesis. Whether satellite cells are generated from a hierarchical stem cell that under- goes asymmetric division to generated committed myoblasts and self-renew and expands by symmetric division or are generated stochastically by a common pool of equipotent stem cells is not known. Without a basic understanding of satellite cell self-renewal it is difficult to extrapolate to an aged environment and attempt to interpret the loss of regenerative capacity. We will compare the turnover and expansion of satellite cells using these methods in young and aged mice that are sedentary, undergoing voluntary exercise and in injured muscles. To accomplish these goals we propose: (1) to establish a system for temporally flexible lineage-tracing in skeletal muscle, (2) to compare satellite cell turnover and clonal expansion in young and aged mice for sedentary, and exercised animals and in injured muscle, and (3) to compare satellite stem cell turnover and clonal expansion in stem cell-engrafted tibialis anterior muscles. These approaches will allow us to experimentally address the mechanisms involved in satellite cell renewal using a combinatorial approach permitting temporally flexible lineage tracing by viral infection and by stem cell transplantation.

Public Health Relevance

Skeletal muscle is essential for respiration, locomotion, and elimination of waste. Severe loss of skeletal muscle is during aging is catastrophic, dramatically reducing overall quality of life and incurring significant health care costs. Severe loss of muscle function that occurs during normal aging is termed sarcopenia. Sarcopenia is likely due to loss of regenerative capacity and the ability of adult muscle stem cells to renew them- selves. We propose research to better understand how adult muscle stem cells are regulated by performing lineage tracing analyses using novel procedures developed in our laboratory to better understand how muscle stem cells repair declines during aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG040074-03
Application #
8509564
Study Section
Special Emphasis Panel (ZAG1-ZIJ-2 (M1))
Program Officer
Williams, John
Project Start
2011-08-01
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$319,857
Indirect Cost
$107,232
Name
University of Colorado at Boulder
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80309
Bernet, Jennifer D; Doles, Jason D; Hall, John K et al. (2014) p38 MAPK signaling underlies a cell-autonomous loss of stem cell self-renewal in skeletal muscle of aged mice. Nat Med 20:265-71