tailieunhanh - Báo cáo Y học: Mitochondrial DNA deletion mutations A causal role in sarcopenia

Mitochondrial DNA (mtDNA) deletion mutations accumulate with age in tissues of a variety of species. Although the relatively low calculated abundance of these deletion mutations in whole tissue homogenates led some investigators to suggest that these mutations do not have any physiological impact, their focal and segmental accumulation suggests that they can, and do, accumulate to levels sufficient to affect the metabolism of a tissue. This phenomenon is most clearly demonstrated in skeletal muscle, where the accumulation of mtDNA deletion mutations remove critical subunits that encode for the electron transport system (ETS) | Eur. J. Biochem. 269 2010-2015 2002 FEBS 2002 doi MINIREVIEW Mitochondrial DNA deletion mutations A causal role in sarcopenia Debbie McKenzie Entela Bua Susan McKiernan Zhengjin Cao Jonathan Wanagat and Judd M. Aiken Department of Animal Health and Biomedical Sciences University of Wisconsin Madison WI USA Mitochondrial DNA mtDNA deletion mutations accumulate with age in tissues of a variety of species. Although the relatively low calculated abundance of these deletion mutations in whole tissue homogenates led some investigators to suggest that these mutations do not have any physiological impact their focal and segmental accumulation suggests that they can and do accumulate to levels sufficient to affect the metabolism of a tissue. This phenomenon is most clearly demonstrated in skeletal muscle where the accumulation of mtDNA deletion mutations remove critical subunits that encode for the electron transport system ETS . In this review we detail and provide evidence for a molecular basis of muscle fiber loss with age. Our data suggest that the mtDNA deletion mutations which are generated in tissues with age cause muscle fiber loss. Within a fiber the process begins with a mtDNA replication error an error that results in a loss of 25-80 of the mitochondrial genome. This smaller genome is replicated and through a process not well understood eventually comprises the majority of mtDNA within the small affected region of the muscle fiber. The preponderance of the smaller genomes results in a dysfunctional ETS in the affected area. As a consequence of both the decline in energy production and the increase in oxidative damage in the region the fiber is no longer capable of selfmaintenance resulting in the observed intrafiber atrophy and fiber breakage. We are therefore proposing that a process contained within a very small region of a muscle fiber can result in breakage and loss of muscle fiber from the tissue. Keywords muscle loss .