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Muscle‐Specific Disruption of Sirt1 Reduces Mitochondrial Function and Increases Reactive Oxygen Species Production
Author(s) -
Menzies Keir J,
Hood David A
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.987.6
Subject(s) - mitochondrial biogenesis , reactive oxygen species , mitochondrion , resveratrol , myosin , skeletal muscle , respiration , wild type , biology , mitochondrial ros , biogenesis , medicine , endocrinology , microbiology and biotechnology , biochemistry , gene , anatomy , mutant
Both caloric restriction and resveratrol, a natural polyphenolic compound, have been shown to activate Sirt1, which in turn extends lifespan and increases mitochondrial content and function. Interestingly, the effects of these treatments and those of exercise, rely on many of the same physiological changes. To further examine the relationship between exercise performance and Sirt1 activity, we produced a skeletal‐muscle specific Sirt1‐deficient mouse. These mice were generated using a myosin light chain‐directed Cre‐loxP targeted mutation of the Sirt1 gene. These mice showed no behavioural or phenotypic abnormalities and had similar body and muscle weights as wild‐type (WT) animals. Isolated muscle mitochondria from Sirt1‐deficient mice exhibited a 45% decline in state 4 respiration along with 4‐fold higher production of reactive oxygen species (ROS) in comparison to WT animals. State 3 respiration was also 70% lower, and was accompanied by a 7‐fold higher ROS production. Despite these findings, over a three week period, Sirt1‐deficient mice ran the same average (12 km/day) and total distances on voluntary running wheels. These data indicate that the absence of Sirt1 results in an impaired capacity for mitochondrial ATP synthesis, along with increased ROS production, which may act as a compensatory signal to maintain mitochondrial biogenesis and voluntary exercise performance. Funded by CIHR..