Differentiation of activated satellite cells in denervated muscle following single fusions in situ and in cell culture |
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Authors: | Email author" target="_blank">Andrei?B?BorisovEmail author Eduard?I?Dedkov Bruce?M?Carlson |
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Institution: | (1) Division of Pediatric Cardiology, Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Room 8200, MSRB III, Ann Arbor, MI 48109-0616, USA;(2) Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109-0616, USA;(3) Institute of Gerontology, University of Michigan Medical School, Ann Arbor, MI 48109-0616, USA |
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Abstract: | Satellite cells represent a cellular source of regeneration in adult skeletal muscle. It remains unclear why a large pool
of stem myoblasts in denervated muscle does not compensate for the loss of muscle mass during post-denervation atrophy. In
this study, we present evidence that satellite cells in long-term denervated rat muscle are able to activate synthesis of
contractile proteins after single fusions in situ. This process of early differentiation leads to formation of abnormally
diminutive myotubes. The localization of such dwarf myotubes beneath the intact basal lamina on the surface of differentiated
muscle fibers shows that they form by fusion of neighboring satellites or by the progeny of a single satellite cell following
one or two mitotic divisions. We demonstrated single fusions of myoblasts using electron microscopy, immunocytochemical labeling
and high resolution confocal digital imaging. Sequestration of nascent myotubes by the rapidly forming basal laminae creates
a barrier that limits further fusions. The recruitment of satellite cells in the formation of new muscle fibers results in
a progressive decrease in their local densities, spatial separation and ultimate exhaustion of the myogenic cell pool. To
determine whether the accumulation of aberrant dwarf myotubes is explained by the intrinsic decline of myogenic properties
of satellite cells, or depends on their spatial separation and the environment in the tissue, we studied the fusion of myoblasts
isolated from normal and denervated muscle in cell culture. The experiments with a culture system demonstrated that the capacity
of myoblasts to synthesize contractile proteins without serial fusions depended on cell density and the availability of partners
for fusion. Satellite cells isolated from denervated muscle and plated at fusion-permissive densities progressed through the
myogenic program and actively formed myotubes, which shows that their myogenic potential is not considerably impaired. The
results of this study suggest that under conditions of denervation, progressive spatial separation and confinement of many
satellite cells within the endomysial tubes of atrophic muscle fibers and progressive interstitial fibrosis are the important
factors that prevent their normal differentiation. Our findings also provide an explanation of why denervated muscle partially
and temporarily is able to restore its functional capacity following injury and regeneration: the release of satellite cells
from their sublaminal location provides the necessary space for a more active regenerative process. |
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Keywords: | Skeletal muscle Satellite cells Myogenesis Denervation-atrophy-regeneration |
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