Long-term caloric restriction increases UCP3 content but decreases proton leak and reactive oxygen species production in rat skeletal muscle mitochondria

Am J Physiol Endocrinol Metab. 2005 Sep;289(3):E429-38. doi: 10.1152/ajpendo.00435.2004. Epub 2005 May 10.


Calorie restriction (CR) without malnutrition increases life span and delays the onset of a variety of diseases in a wide range of animal species. However, the mechanisms responsible for the retardation of aging with CR are poorly understood. We proposed that CR may act, in part, by inducing a hypometabolic state characterized by decreased reactive oxygen species (ROS) production and mitochondrial proton leak. Here, we examine the effects of long-term CR on whole animal energetics as well as muscle mitochondrial energetics, ROS production, and ROS damage. CR was initiated in male FBNF1 rats at 6 mo of age and continued for 12 or 18 mo. Mean whole body VO2 was 34.6 (P < 0.01) and 35.6% (P < 0.001) lower in CR rats than in controls after 12 and 18 mo of CR, respectively. Body mass-adjusted VO2 was 11.1 and 29.5% lower (both P < 0.05) in CR rats than in controls after 12 and 18 mo of CR. Muscle mitochondrial leak-dependent (State 4) respiration was decreased after 12 mo compared with controls; however, after 18 mo of CR, there were slight but not statistically significant differences. Proton leak kinetics were affected by 12 mo of CR such that leak-dependent respiration was lower in CR mitochondria only at protonmotive force values exceeding 170 mV. Mitochondrial H2O2 production and oxidative damage were decreased by CR at both time points and increased with age. Muscle UCP3 protein content increased with long-term CR, consistent with a role in protection from ROS but inconsistent with the observed decrease or no change in proton leak.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aging / metabolism
  • Animals
  • Body Weight
  • Caloric Restriction*
  • Carrier Proteins / metabolism*
  • Heart / anatomy & histology
  • Hydrogen Peroxide / metabolism
  • Ion Channels
  • Kidney / anatomy & histology
  • Kidney / metabolism
  • Lipid Peroxidation
  • Liver / anatomy & histology
  • Liver / metabolism
  • Male
  • Mitochondria / metabolism*
  • Mitochondrial Proteins
  • Muscle, Skeletal / metabolism*
  • Myocardium / metabolism
  • Organ Size
  • Oxidative Phosphorylation
  • Oxygen Consumption / physiology
  • Protons
  • Rats
  • Rats, Inbred Strains
  • Reactive Oxygen Species / metabolism*
  • Uncoupling Protein 3


  • Carrier Proteins
  • Ion Channels
  • Mitochondrial Proteins
  • Protons
  • Reactive Oxygen Species
  • Ucp3 protein, rat
  • Uncoupling Protein 3
  • Hydrogen Peroxide