Mitochondrial biogenesis and PGC-1α deacetylation by chronic treadmill exercise: Differential response in cardiac and skeletal muscle

Institute of Physiology, Justus Liebig University Giessen, Aulweg 129, 35392 Giessen, Germany.
Archiv für Kreislaufforschung (Impact Factor: 5.41). 08/2011; 106(6):1221-34. DOI: 10.1007/s00395-011-0213-9
Source: PubMed


Posttranslational modifications of the transcriptional coactivator PGC-1α by the deacetylase SIRT1 and the kinase AMPK are involved in exercise-induced mitochondrial biogenesis in skeletal muscle. However, similar investigations have not been performed in the left ventricle (LV). Here, we tested whether treadmill training (12 weeks) modifies PGC-1α and mitochondrial biogenesis in gastrocnemius muscle and LV of C57BL/6 J wild-type mice and IL-6-deficient mice with a reported impairment in muscular AMPK activation similarly. Physical activity lowered the plasma insulin and glucose in both mouse strains, suggesting improved insulin sensitivity. The gastrocnemius muscle of IL-6-deficient mice showed reduced mitochondrial respiration and enzyme activity, which was partially normalized after training. Chronic exercise enhanced the mitochondrial biogenesis in gastrocnemius muscle as indicated by increased mRNA or protein expression of primary mitochondrial transcripts, higher mtDNA content and increased citrate synthase activity. Parallel to these changes, we observed AMPK activation, SIRT1 induction and PGC-1α deacetylation. Chronic treadmill training resulted in a mild cardiac hypertrophy in both mouse strains. However, none of these changes observed in skeletal muscle were detected in the LV (both mouse strains) with the exception of AMPK activation and a mildly increased succinate-dependent respiration. Thus, chronic endurance training induces a sustained mitochondrial biogenic response in mouse gastrocnemius muscle but not in the LV. Although AMPK activation occurs in both muscular organs, the absence of SIRT1-dependent PGC-1α deacetylation may be responsible for this significant difference. AMPK activation by IL-6 appears to be dispensable for the mitochondrial biogenic responses to chronic treadmill exercise.

Download full-text


Available from: Ling li, Nov 17, 2014
  • Source
    • "It has been observed that even cardiac and skeletal muscle exhibit different responses to chronic exercise [20] and vitamin E is able to reduce heart oxidative stress due to several conditions, among which acute exercise [21] and ischemia–reperfusion [22] Q1 . Conversely, data concerning the effects of vitamin E treatment on cardiac tissue from trained animals are lacking. "
    [Show abstract] [Hide abstract]
    ABSTRACT: We investigated whether reactive oxygen species are involved in heart adaptive responses administering a vitamin E enriched diet to trained rats. On homogenates and/or mitochondria from rat hearts we determined aerobic capacity, tissue level of mitochondrial proteins and expression of cytochrome c and factors (PGC-1, NRF-1, and NRF-2) involved in mitochondrial biogenesis. We also determined oxidative damage, glutathione peroxidase and reductase activities, glutathione content, mitochondrial ROS release rate and susceptibility to in vitro oxidative challenge. GSH content was not affected by both training and antioxidant supplementation. Conversely, antioxidant supplementation prevented metabolic adaptations to training, such as the increases in oxidative capacity, tissue content of mitochondrial proteins, and cytochrome c expression, attenuated some protective adaptations such as the increase in antioxidant enzyme activities, and did not modify the decrease in ROS release by succinate supplemented mitochondria. Moreover, vitamin E prevented the training-linked increase in tissue capacity to oppose an oxidative attach. The antioxidant effects were associated with decreased levels of PGC-1, NRF-1, and NRF-2 expression. Our results support the idea that some heart adaptive responses to training depend on reactive oxygen species produced during the exercise sessions and are mediated by the increase in PGC-1 expression which is involved in both regulation of respiratory capacity and antioxidant protection. However, vitamin inability to prevent some adaptations suggests that other signaling pathways impinging on PGC-1 can modify the response to the antioxidant integration.
    Full-text · Article · Oct 2015 · Free Radical Research
  • Source
    • "Exercise training enhances mitochondrial biogenesis and performance in skeletal muscle (Irrcher et al., 2003), but not in the heart (Li et al., 2011). Whether the same is true in T2DM hearts is unclear. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Current scientific debates center on the impact of lipids and mitochondrial function on diverse aspects of human health, nutrition and disease, among them the association of lipotoxicity with the onset of insulin resistance in skeletal muscle, and with heart dysfunction in obesity and diabetes. Mitochondria play a fundamental role in aging and in prevalent acute or chronic diseases. Lipids are main mitochondrial fuels however these molecules can also behave as uncouplers and inhibitors of oxidative phosphorylation. Knowledge about the functional composition of these contradictory effects and their impact on mitochondrial-cellular energetics/redox status is incomplete. Cells store fatty acids (FAs) as triacylglycerol and package them into cytoplasmic lipid droplets (LDs). New emerging data shows the LD as a highly dynamic storage pool of FAs that can be used for energy reserve. Lipid excess packaging into LDs can be seen as an adaptive response to fulfilling energy supply without hindering mitochondrial or cellular redox status and keeping low concentration of lipotoxic intermediates. Herein we review the mechanisms of action and utilization of lipids by mitochondria reported in liver, heart and skeletal muscle under relevant physiological situations, e.g., exercise. We report on perilipins, a family of proteins that associate with LDs in response to loading of cells with lipids. Evidence showing that in addition to physical contact, mitochondria and LDs exhibit metabolic interactions is presented and discussed. A hypothetical model of channeled lipid utilization by mitochondria is proposed. Direct delivery and channeled processing of lipids in mitochondria could represent a reliable and efficient way to maintain reactive oxygen species (ROS) within levels compatible with signaling while ensuring robust and reliable energy supply.
    Full-text · Article · Jul 2014 · Frontiers in Physiology
  • Source
    • "The blood count and plasma lipid profile were not different between IL-6−/− and WT animals (Table 1). As it was reported that IL-6−/− mice developed age-related obesity that might contribute to their reduced exercise performance [7], [11], [15], we monitored their body weight and found no difference (P>0.05) between IL-6−/− and WT mice both at the age of 10 and 12 months. Since reduced exercise performance of IL-6−/− mice could also result from increased energy dissipation, we measured their body temperature which was not different both at rest (Figure 3C) and just after exercise (Figure 3D) between IL-6−/− and WT mice. "
    [Show abstract] [Hide abstract]
    ABSTRACT: It has been reported that IL-6 knockout mice (IL-6−/−) possess lower endurance capacity than wild type mice (WT), however the underlying mechanism is poorly understood. The aim of the present work was to examine whether reduced endurance running capacity in IL-6−/− mice is linked to impaired maximal oxygen uptake (V′O2max), decreased glucose tolerance, endothelial dysfunction or other mechanisms. Maximal running velocity during incremental running to exhaustion was significantly lower in IL-6−/− mice than in WT mice (13.00±0.97 m.min−1 vs. 16.89±1.15 m.min−1, P<0.02, respectively). Moreover, the time to exhaustion during running at 12 m.min−1 in IL-6−/− mice was significantly shorter (P<0.05) than in WT mice. V′O2max in IL-6−/− (n = 20) amounting to 108.3±2.8−1.min−1 was similar as in WT mice (n = 22) amounting to 113.0±1.8−1.min−1, (P = 0.16). No difference in maximal COX activity between the IL-6−/− and WT mice in m. soleus and m. gastrocnemius was found. Moreover, no impairment of peripheral endothelial function or glucose tolerance was found in IL-6−/− mice. Surprisingly, plasma lactate concentration during running at 8 m.min−1 as well at maximal running velocity in IL-6−/− mice was significantly lower (P<0.01) than in WT mice. Interestingly, IL-6−/− mice displayed important adaptive mechanisms including significantly lower oxygen cost of running at a given speed accompanied by lower expression of sarcoplasmic reticulum Ca2+-ATPase and lower plasma lactate concentrations during running at submaximal and maximal running velocities. In conclusion, impaired endurance running capacity in IL-6−/− mice could not be explained by reduced V′O2max, endothelial dysfunction or impaired muscle oxidative capacity. Therefore, our results indicate that IL-6 cannot be regarded as a major regulator of exercise capacity but rather as a modulator of endurance performance. Furthermore, we identified important compensatory mechanism limiting reduced exercise performance in IL-6−/− mice.
    Full-text · Article · Feb 2014 · PLoS ONE
Show more