Endurance training ameliorates the metabolic and performance characteristics of circadian Clock mutant mice.

J Appl Physiol (1985) 2013 Apr 21;114(8):1076-84. Epub 2013 Feb 21.

Muscle Health Research Center, York University, Toronto, Ontario, Canada.

Circadian locomotor output cycles kaput (CLOCK) is a nuclear transcription factor that is a component of the central autoregulatory feedback loop that governs the generation of biological rhythms. Homozygous Clock mutant mice contain a truncated CLOCK(Δ19) protein within somatic cells, subsequently causing an impaired ability to rhythmically transactivate circadian genes. The present study sought to investigate whether the Clock mutation affects mitochondrial physiology within skeletal muscle, as well as the responsiveness of these mutant animals to adapt to a chronic voluntary endurance training protocol. Within muscle, Clock mutant mice displayed 44% and 45% reductions in peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC-1α) and mitochondrial transcription factor-A protein content, respectively, and an accompanying 16% decrease in mitochondrial content, as determined by cytochrome c oxidase enzyme activity. These decrements contributed to a 50% decrease in exercise tolerance in Clock mutant mice. Interestingly, the Clock mutation did not appear to alter subsarcolemmal or intermyofibrillar mitochondrial respiration within muscle or systemic glucose tolerance. Daily locomotor activity levels were similar between wild-type and Clock mutant mice throughout the training protocol. Endurance training ameliorated the decrease in PGC-1α protein expression and mitochondrial content in the Clock mutant mice, eliciting a 2.9-fold improvement in exercise tolerance. Thus our data suggest that a functional CLOCK protein is essential to ensure the maintenance of mitochondrial content within muscle although the absence of a functional CLOCK protein does not impair the ability of animals to adapt to chronic exercise.

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http://dx.doi.org/10.1152/japplphysiol.01505.2012DOI Listing
April 2013

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