This project will explore a novel mechanism potentially contributing both to muscle atrophy and increased muscle lipid with age. Our work shows that in the mouse, the progenitors present in muscle that are primarily responsible for postnatal muscle growth, repair, and maintenance, activate an adipocyte-like gene program with age. The balance between myogenic and adipogenic potential appears to be regulated by Wnt signaling. In fact, the constellation of Wnt ligands present and the signaling pathways activated appear to crosstalk to control muscle size and lipid content. Thus, Wnt signaling may provide the mechanistic link whereby exercise influences both muscle properties. We hypothesize that Wnt signaling is altered in myogenic progenitors as a function of age contributing to impaired muscle function through loss of muscle mass and increased intramyocellular lipid following injury. In addition, intermyocellular lipid increases with age and we will assess the cellular properties of myofibroblasts to test the hypothesis that changes in their potential through altered Wnt signaling may contribute to lipid accumulation surrounding myofibers.
In Aim 1 we will identify the signaling pathways that account for the distinct function of WntlOb in repressing adipogenic gene expression compared to other Wnts that promote myogenic differentiation and hypertrophy, and determine the role of changes in Wnt signaling in altering myogenic progenitor potential with age. Myofibroblasts will be characterized in vitro in Aim 2 to determine if adipogenic potential increases with age, potentially contributing to intermyocellular lipid. Co-culture of myogenic progenitors and myofibroblasts from different aged mice will determine if age affects their interaction.
In Aim 3, myogenic progenitors will be """"""""exercised"""""""" in vitro with a Flexcell stretcher to attempt to alter adipogenic potential. Lipid accumulation and myotube size will be quantified to determine if the effects of exercise differ with age through altered signaling. Preliminary data in human myogenic progenitors suggest that age also increases their adipogenic potential and focused analyses will be translated into humans.
In Aim 4, myogenic progenitors and myofibroblasts will be isolated from older compared to younger humans to characterize myogenic and adipogenic differentiation potential that will be correlated with age, muscle adiposity, size and strength. The effects of an exercise regimen on muscle properties in vivo will be assessed in relation to changes in myogenic progenitor potential in vitro. We will examine the underlying mechanisms involved, and whether response differs with age. The long term goal of this research is to characterize changes in cell fate with age and determine their contribution to impaired muscle function in the elderly. Using this information, rational new strategies for frailty prevention can be designed and tested. ? ? ? ?
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