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.

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Available from: Ling li, Nov 17, 2014
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    • "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. "
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    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.
    Frontiers in Physiology 07/2014; 5:282. DOI:10.3389/fphys.2014.00282 · 3.53 Impact Factor
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    • "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. "
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    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.
    PLoS ONE 02/2014; 9(2):e88333. DOI:10.1371/journal.pone.0088333 · 3.23 Impact Factor
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    • "However, endurance training still enhanced mitochondrial biogenesis in gastrocnemius muscle. AMPK activation by IL-6 appeared to be dispensable for the mitochondrial biogenic responses to chronic treadmill exercise (Li et al., 2011a). The key protein deacetylase, sirtuin 1 (SIRT1), is a master regulator of mitochondrial biogenesis in skeletal muscle, primarily via its ability to deacetylate and activate PGC-1α (Aquilano et al., 2010;Gurd, 2011;Li et al., 2011b). "
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    ABSTRACT: During endurance and resistance exercise training, AMPK and mTOR signaling were known as selective pathways implicating the differentiation of exercise-induced phenotype in skeletal muscle. Among the previous studies, however, the differences in exercise protocol, the individuality and the genetic heterogeneity within species make it difficult to reach a consistent conclusion in the roles of AMPK and mTOR signaling. In this review, we aim not to reanalyze the previous articles and present the research progress of AMPK and mTOR signaling in exercise, but to propose an abstract general hypothesis for exercise-induced phenotype. Generally, exercise- induced skeletal muscle phenotype is independent of one and a few genes, proteins and signaling pathways. Convergent adaptation will better summarize the specificity of skeletal muscle phenotype in response to a single mode of exercise. Backward adaptation will open a new concept to illustrate the process of exercise-induced adaptation, such as mitochondrial quality control and muscle mass homeostasis.
    SpringerPlus 12/2013; 2(1):693. DOI:10.1186/2193-1801-2-693
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