This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. While the mechanisms of age-associated sarcopenia (i.e. loss of skeletal muscle mass and contractile capacity) are poorly understood, it is well known that advanced saropenia leads to functional decline and to the frailty phenotype which confers high risk for dependence, disability, hospitalization, and mortality. Morphologic and functional indices of sarcopenia appear to accelerate beyond age 50; however, the specific pathophysiology triggering the decline is as yet unclear. Skeletal muscle satellite cells play a requisite role in maintaining muscle mass during repair/regeneration and we will test the hypothesis that blunted satellite cell activity with age is a key modulator of age-related sarcopenia. We predict the progressive age-related decrease in muscle mass is the cumulative result of repeated episodes of incomplete repair consequent to a Limited satellite cell activity. We will evaluate myostatin as a likely mediator of satellite cell suppression with age and we predict satellite cell suppression will lead to a blunted myogenic response to an acute loading bout. We expect this to be most notable among individuals with advanced sarcopenia as characterized by our model of the sarcopenic phenotype. The overall goals of this research project are therefore to characterize the sarcopenia timecourse, its molecular triggers, and the phenotype predictive of functional decline. Our human experimental design runs the gamut as it includes in vivo physiologic testing, immunohistochemical studies in situ, biochemical studies, and in vitro studies of satellite cells in primary culture. The proposed translational research project would provide the first comprehensive assessment of sarcopenia etiology and clinical outcomes using a single cohort of human subjects spanning the adult age range. Overall Hypothesis. We hypothesize the type II myofiber atrophy and loss of myofibers, which are characteristic of the sarcopenic phenotype, are mediated in part by a reduced myogenic response to loading. We will evaluate myostatin as a likely mediator of the blunted myogenic response. Irrespective of chronological age, we hypothesize that this inhibition of myogenesis is most prevalent in individuals with advanced sarcopenia. We will test the following specific hypotheses in adults 30-70+ years of age by studying 3 age groups: Younger (YG, 30-50 yr), Young Old (YO, 55-65 yr), and Older (OL, 70+ yr) adults. Hypothesis 1. Irrespective of chronological age, we hypothesize that patients sharing a common sarcopenic phenotype (based on morphologic and performance indices) will demonstrate a blunted myogenic response to an acute resistance exercise loading bout. We predict exercise-induced expression of the myogenic regulatory factors (myf-6, myogenin, MyoD), load-sensitive IGF-I, and expression of the cyclins B1 and Dl (as indices of satellite cell activation) will be hampered in these patients compared to the non-sarcopenic phenotype. Hypothesis 2. We predict reductions in satellite cell activity with advancing age will be associated with age-related increases in myostatin protein and gene expression. Reductions in the muscle satellite cell population will be detected in age groups beyond age 50 as noted in situ by reduced satellite cell frequency on tissue sections and in vitro by a lower satellite cell yield in culture per unit muscle mass and a reduced number of population doubling to senescence. In primary culture we predict an age-related reduction in the rate of basal proliferation and differentiation (ie. myotube formation). Given appropriate mitogenic stimuli (e.g. IGF-I, bFGF), however, we expect a similar proliferative response in cultured satellite cells from individuals of all ages. These novel data will provide a much needed foundation in sarcopenia research and future clinical applications.
Showing the most recent 10 out of 570 publications
