Role of telomere shortening in skeletal muscle aging

2011 new Scholar Award in aging

Aging is characterized by a progressive decline of tissue function associated with loss of regenerative potential. With age stem cell compartments are progressively less efficient in maintaining tissue homeostasis, and tissues undergo atrophy. These changes have been associated with critical telomere shortening. While animal models lacking telomerase activity have enabled the characterization of the stem cell functional decline in high proliferative organs, these animals do not provide a useful tool for studying slow-turnover tissues such as skeletal muscle. This is due to the premature effects of high proliferative organ dysfunction on organismal life-span. Indeed, while recent studies have identified systemic and microenviromental factors influencing the functional decline of skeletal muscle stem cells, the role of their cell autonomous changes associated with the aging process are still largely unexplored. We have recently generated a novel mouse model that exhibits features of premature skeletal muscle aging, including atrophy, defects in proliferation of muscle stem cells, and with age an overall reduction of their numbers. This was associated with critical telomere shortening already at young age. These results provide the first evidence of a major role of telomerase in regulating skeletal muscle stem cell function. This indicates that our animal model is a useful tool to unravel the molecular mechanisms associated with skeletal muscle aging. The overall goal of this proposal is to elucidate the role of telomere shortening in skeletal muscle aging and investigate the involvement of the p53/p21 axis in directing cellular senescence in muscle stem cells.

Alessandra Sacco Ph.D.
Sanford-Burnham Medical Research Institute