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Loss of a single allele for Ku80 leads to progenitor dysfunction and accelerated aging in skeletal muscle.

ABSTRACT: Muscle wasting is a major cause of morbidity in the elderly. Ku80 is required for DNA double strand repair and is implicated in telomere maintenance. Complete loss-of-function leads to reduced post-natal growth and severe progeria in mice. We examined the role of Ku80 in age-related skeletal muscle atrophy. While complete loss of Ku80 leads to pronounced aging in muscle as expected, accompanied by accumulation of DNA damage, loss of a single allele is sufficient to accelerate aging in skeletal muscle although post-natal growth is normal. Ku80 heterozygous muscle shows no DNA damage accumulation but undergoes premature telomere shortening that alters stem cell self-renewal through stress response pathways including p53. These data reveal an unexpected requirement for both Ku80 alleles for optimal progenitor function and prevention of early onset aging in muscle, as well as providing a useful model for therapeutic approaches.

SUBMITTER: Didier N

PROVIDER: S-EPMC3491824 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Loss of a single allele for Ku80 leads to progenitor dysfunction and accelerated aging in skeletal muscle.

Didier Nathalie N Hourdé Christophe C Amthor Helge H Marazzi Giovanna G Sassoon David D

EMBO molecular medicine 20120823 9

Muscle wasting is a major cause of morbidity in the elderly. Ku80 is required for DNA double strand repair and is implicated in telomere maintenance. Complete loss-of-function leads to reduced post-natal growth and severe progeria in mice. We examined the role of Ku80 in age-related skeletal muscle atrophy. While complete loss of Ku80 leads to pronounced aging in muscle as expected, accompanied by accumulation of DNA damage, loss of a single allele is sufficient to accelerate aging in skeletal m ...[more]

PMID: 22915554

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Project description:ObjectiveSkeletal muscle oxidative capacity is central to physical activity, exercise capacity and whole-body metabolism. The three estrogen-related receptors (ERRs) are regulators of oxidative metabolism in many cell types, yet their roles in skeletal muscle remain unclear. The main aim of this study was to compare the relative contributions of ERRs to oxidative capacity in glycolytic and oxidative muscle, and to determine defects associated with loss of skeletal muscle ERR function.MethodsWe assessed ERR expression, generated mice lacking one or two ERRs specifically in skeletal muscle and compared the effects of ERR loss on the transcriptomes of EDL (predominantly glycolytic) and soleus (oxidative) muscles. We also determined the consequences of the loss of ERRs for exercise capacity and energy metabolism in mice with the most severe loss of ERR activity.ResultsERRs were induced in human skeletal muscle in response to an exercise bout. Mice lacking both ERRα and ERRγ (ERRα/γ dmKO) had the broadest and most dramatic disruption in skeletal muscle gene expression. The most affected pathway was "mitochondrial function", in particular Oxphos and TCA cycle genes, and transcriptional defects were more pronounced in the glycolytic EDL than the oxidative soleus. Mice lacking ERRβ and ERRγ, the two isoforms expressed highly in oxidative muscles, also exhibited defects in lipid and branch chain amino acid metabolism genes, specifically in the soleus. The pronounced disruption of oxidative metabolism in ERRα/γ dmKO mice led to pale muscles, decreased oxidative capacity, histochemical patterns reminiscent of minicore myopathies, and severe exercise intolerance, with the dmKO mice unable to switch to lipid utilization upon running. ERRα/γ dmKO mice showed no defects in whole-body glucose and energy homeostasis.ConclusionsOur findings define gene expression programs in skeletal muscle that depend on different combinations of ERRs, and establish a central role for ERRs in skeletal muscle oxidative metabolism and exercise capacity. Our data reveal a high degree of functional redundancy among muscle ERR isoforms for the protection of oxidative capacity, and show that ERR isoform-specific phenotypes are driven in part, but not exclusively, by their relative levels in different muscles.

Dataset Information

Loss of a single allele for Ku80 leads to progenitor dysfunction and accelerated aging in skeletal muscle.

Publications

Loss of a single allele for Ku80 leads to progenitor dysfunction and accelerated aging in skeletal muscle.

Similar Datasets

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