Sarcopenia, the age-associated loss of skeletal muscle mass and strength, is linked to a decreased quality of life for, an increased incidence of disability, loss of independent living, and increased risk for morbidity for the elderly. The activation, proliferation, and differentiation of satellite cells is a necessary progression for the maintenance of muscle mass, and decreases in satellite cell function, including satellite cell activation, have been reported with aging. In this regard, satellite cell activation is an appropriate target for therapeutic interventions to ameliorate the deleterious effects of sarcopenia, therefore, the long-term objectives are to better understand satellite cell activation. The progression from quiescence to activation is characterized by increased cell cycle entry and an increase in metabolism. Since hypoxia-inducible factor-1 (HIF-1) is known for its ability to transactivate genes important for glycolytic metabolism, a plausible hypothesis is that HIF-1 is important for increased in satellite cell activation, and may be involved in decreased satellite cell activation that occurs with aging. To test these hypotheses, hepatocyte growth factor (HGF), which is well-known for its ability to activate satellite cells, and myostatin, a negative regulator of satellite cell activation, will be used to determine the importance of HIF-1 activity and increased cell metabolism in satellite cell activation, and this information will be used to determine mechanisms underlying delayed satellite cell activation with aging.
The specific aims of this proposal are to 1) Determine the role of HIF-1 during HGF-induced increases in satellite cell activation, 2) Determine the role of HIF-1 during myostatin-induced decreases in satellite cell activation, and 3) Determine the importance of HIF-1 in delayed satellite cell activation with aging. Satellite cell and single fiber cultures, and whole skeletal muscle models in adult and old animals will be used to accomplish these aims. HGF, myostatin, MAPK/ERK, Smad, and HIF-1 activities will be manipulated pharmocologically and/or genetically in conjunction with HIF-1 -dependent promoter activity, mRNA, and protein measurements. Since the function of HIF-1 during satellite cell activation has not previously been determined, mRNA levels of key HIF-1 target genes will be measured in addition to chromatin immunoprecipitatioin. Satellite cell (adult muscle stem cell) activation is impaired in aging and may be a contributor to the loss of skeletal muscle mass that occurs with aging. This research is directed towards increasing the understanding how two growth factors affect satellite cell activation, HGF and myostatin, and if these growth factors work through the transcription factor hypoxia-inducible factor (HIF-1). ? ? ?
| Rathbone, Christopher R; Yamanouchi, Keitaro; Chen, Xiaoyu K et al. (2011) Effects of transforming growth factor-beta (TGF-?1) on satellite cell activation and survival during oxidative stress. J Muscle Res Cell Motil 32:99-109 |
