Increased fatigue resistance linked to Ca2+-stimulated mitochondrial biogenesis in muscle fibres of cold-acclimated mice

J Physiol. 2010 Nov 1;588(Pt 21):4275-88. doi: 10.1113/jphysiol.2010.198598.


Mammals exposed to a cold environment initially generate heat by repetitive muscle activity (shivering). Shivering is successively replaced by the recruitment of uncoupling protein-1 (UCP1)-dependent heat production in brown adipose tissue. Interestingly, adaptations observed in skeletal muscles of cold-exposed animals are similar to those observed with endurance training. We hypothesized that increased myoplasmic free [Ca2+] ([Ca2+]i) is important for these adaptations. To test this hypothesis, experiments were performed on flexor digitorum brevis (FDB) muscles, which do not participate in the shivering response, of adult wild-type (WT) and UCP1-ablated (UCP1-KO) mice kept either at room temperature (24°C) or cold-acclimated (4°C) for 4-5 weeks. [Ca2+]i (measured with indo-1) and force were measured under control conditions and during fatigue induced by repeated tetanic stimulation in intact single fibres. The results show no differences between fibres from WT and UCP1-KO mice. However, muscle fibres from cold-acclimated mice showed significant increases in basal [Ca2+]i (∼50%), tetanic [Ca2+]i (∼40%), and sarcoplasmic reticulum (SR) Ca2+ leak (∼fourfold) as compared to fibres from room-temperature mice. Muscles of cold-acclimated mice showed increased expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and increased citrate synthase activity (reflecting increased mitochondrial content). Fibres of cold-acclimated mice were more fatigue resistant with higher tetanic [Ca2+]i and less force loss during fatiguing stimulation. In conclusion, cold exposure induces changes in FDB muscles similar to those observed with endurance training and we propose that increased [Ca2+]i is a key factor underlying these adaptations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological / physiology*
  • Animals
  • Calcium / physiology*
  • Cold Temperature*
  • Female
  • Ion Channels / genetics
  • Ion Channels / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria, Muscle / physiology*
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / physiology
  • Models, Animal
  • Muscle Fatigue / physiology*
  • Muscle Fibers, Skeletal / physiology*
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Shivering / physiology
  • Trans-Activators / physiology
  • Transcription Factors
  • Uncoupling Protein 1


  • Ion Channels
  • Mitochondrial Proteins
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Trans-Activators
  • Transcription Factors
  • Ucp1 protein, mouse
  • Uncoupling Protein 1
  • Calcium