Caloric Restriction Protects Mitochondrial Function with Aging in Skeletal and Cardiac Muscles
R.T. Hepple, D.J. Baker, M. McConkey, T. Murynka, and R. Norris
University of Calgary, Faculty of Kinesiology, 2500 University Dr. NW, Calgary, AB, CANADA T2N 1N4
Aging is associated with impairment in mitochondrial function that has
been implicated in tissue dysfunction particularly in post-mitotic
tissues. We examine here the impact of long term caloric restriction
(CR), begun in juvenile male Fischer 344 X Brown Norway F1-hybrid rats,
on the age-associated decline in oxidative capacity and mitochondrial
function across a range of metabolic and contractile phenotypes in
skeletal muscles, and in the most highly aerobic muscle, heart.
Interestingly, in both skeletal muscle and heart, in vitro cytochrome
oxidase activity is lower in young adult CR animals despite normal
aerobic function in situ and in vivo, indicative of a higher oxygen
affinity of mitochondria in CR. On the other hand, in contrast to the
25-46% decline in markers of oxidative capacity in cardiac and various
distal hindlimb skeletal muscles of ad libitum fed (AL) animals between
8-10 mo (young adulthood) and 35 mo (senescence), there is no decline
in CR across the same absolute age (35 mo old) or relative age (35%
survival rate: 35 mo of age in AL, 40 mo of age in CR) range. In
seeking to explain the means by which CR maintains oxidative capacity
with aging, we show that CR acts principally to maintain mitochondrial
function rather than content (citrate synthase protein not affected by
age or dietary treatment, despite cytochrome oxidase decline with aging
in AL), and that this is unrelated to the frequency of mtDNA deletions
(although CR protects oxidative capacity in plantaris muscle and mixed
gastrocnemius muscle with aging, the frequency of mtDNA deletion
fragments is lower only in the plantaris muscle of aged CR animals) but
rather is consistent with a maintained drive on mitochondrial
biogenesis (more gradual decline in PGC-1 gene expression with aging in
CR). Thus, our results show that CR completely prevents the
age-associated decline in oxidative capacity in heart and skeletal
muscles at least out to 35% survival rate in male F344BN rats, and that
this effect is consistent with a protection of mitochondrial function
secondary to a better maintained drive on mitochondrial biogenesis.
Key words:
mitochondria, caloric restriction, mitochondrial DNA, mitochondrial biogenesis
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