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1 Institute of Gerontology, University of Michigan, Ann Arbor, MI, USA; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
2 Institute of Gerontology, University of Michigan, Ann Arbor, MI, USA; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
3 Institute of Gerontology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA
4 Institute of Gerontology, University of Michigan, Ann Arbor, MI, USA; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
* To whom correspondence should be addressed. E-mail: kostromi{at}umich.edu.
Loss of innervation in skeletal muscles leads to degeneration, atrophy, and loss of force. These dramatic changes are reflected in modifications of the mRNA expression of a large number of genes. Our goal was to clarify the broad spectrum of molecular events associated with long-term denervation of skeletal muscles. A microarray study compared gene expression profiles of 2 month denervated and control EDL muscles from 6 month old rats. The study identified 121 genes with increased and 7 genes with decreased mRNA expression. The expression of 107 of these genes had not been identified previously as changed after denervation. Many of the genes identified were genes that are highly expressed in skeletal muscles during embryonic development, down-regulated in adults and upregulated after denervation of muscle fibers. Electrical stimulation of denervated muscles preserved muscle mass and maximal force at levels similar to those in the control muscles. To understand the processes underlying the effect of electrical stimulation on denervated skeletal muscles, mRNA and protein expression of a number of genes, identified by the microarray study, was compared. The hypothesis was that loss of nerve action potentials and muscle contractions after denervation play the major roles in up-regulation of gene expression in skeletal muscles. With electrical stimulation of denervated muscles the expression levels for these genes were significantly down-regulated, consistent with the hypothesis that loss of action potentials and/or contractions contribute to the alterations in gene expression in denervated skeletal muscles.
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