Diminished mitochondrial oxidative phosphorylation and aerobic capacity are associated with reduced longevity. We tested whether resveratrol (RSV), which is known to extend lifespan, impacts mitochondrial function and metabolic homeostasis. Treatment of mice with RSV significantly increased their aerobic capacity, as evidenced by their increased running time and consumption of oxygen in muscle fibers. RSV's effects were associated with an induction of genes for oxidative phosphorylation and mitochondrial biogenesis and were largely explained by an RSV-mediated decrease in PGC-1alpha acetylation and an increase in PGC-1alpha activity. This mechanism is consistent with RSV being a known activator of the protein deacetylase, SIRT1, and by the lack of effect of RSV in SIRT1(-/-) MEFs. Importantly, RSV treatment protected mice against diet-induced-obesity and insulin resistance. These pharmacological effects of RSV combined with the association of three Sirt1 SNPs and energy homeostasis in Finnish subjects implicates SIRT1 as a key regulator of energy and metabolic homeostasis.

The goal of the study was to determine the effects of continuous (CT) vs. intermittent (IT) training yielding identical mechanical work and training duration on skeletal muscle and cardiorespiratory adaptations in sedentary subjects. Eleven subjects (6 men and 5 women, 45 +/- 3 years) were randomly assigned to either of the two 8-wk training programs in a cross-over design, separated by 12 wk of detraining. Maximal oxygen uptake (Vo2max) increased after both trainings (9% with CT vs. 15% with IT), whereas only IT was associated with faster Vo2 kinetics (tau: 68.0 +/- 1.6 vs. 54.9 +/- 0.7 s, P < 0.05) measured during a test to exhaustion (TTE) and with improvements in maximal cardiac output (Qmax, from 18.1 +/- 1.1 to 20.1 +/- 1.2 l/min; P < 0.01). Skeletal muscle mitochondrial oxidative capacities (Vmax) were only increased after IT (3.3 +/- 0.4 before and 4.5 +/- 0.6 micromol O2 x min(-1) x g dw(-1) after training; P < 0.05), whereas capillary density increased after both trainings, with a two-fold higher enhancement after CT (+21 +/- 1% for IT and +40 +/- 3% after CT, P < 0.05). The gain of Vmax was correlated with the gain of TTE and the gain of Vo2max with IT. The gain of Qmax was also correlated with the gain of VO2max. These results suggest that fluctuations of workload and oxygen uptake during training sessions, rather than exercise duration or global energy expenditure, are key factors in improving muscle oxidative capacities. In an integrative view, IT seems optimal in maximizing both peripheral muscle and central cardiorespiratory adaptations, permitting significant functional improvement. These data support the symmorphosis concept in sedentary subjects.

Duchenne muscular dystrophy (DMD) is characterized by myofiber death from apoptosis or necrosis, leading in many patients to fatal respiratory muscle weakness. Among other pathological features, DMD muscles show severely deranged metabolic gene regulation and mitochondrial dysfunction. Defective mitochondria not only cause energetic deficiency, but also play roles in promoting myofiber atrophy and injury via opening of the mitochondrial permeability transition pore. Autophagy is a bulk degradative mechanism that serves to augment energy production and eliminate defective mitochondria (mitophagy). We hypothesized that pharmacological activation of AMP-activated protein kinase (AMPK), a master metabolic sensor in cells and on-switch for the autophagy-mitophagy pathway, would be beneficial in the mdx mouse model of DMD. Treatment of mdx mice for 4 weeks with an established AMPK agonist, AICAR (5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside), potently triggered autophagy in the mdx diaphragm without inducing muscle fiber atrophy. In AICAR-treated mdx mice, the exaggerated sensitivity of mdx diaphragm mitochondria to calcium-induced permeability transition pore opening was restored to normal levels. There were associated improvements in mdx diaphragm histopathology and in maximal force-generating capacity, which were not linked to increased mitochondrial biogenesis or up-regulated utrophin expression. These findings suggest that agonists of AMPK and other inducers of the autophagy-mitophagy pathway can help to promote the elimination of defective mitochondria and may thus serve as useful therapeutic agents in DMD.

Our findings identify statins as a new activating factor of cardiac mitochondrial biogenesis and antioxidant capacities, and suggest the importance of ROS/PGC-1 signalling pathway as a key element in regulation of mitochondrial function in cardiac as well as skeletal muscles.

Improvement of exercise capacity by continuous (CT) versus interval training (IT) remains debated. We tested the hypothesis that CT and IT might improve peripheral and/or central adaptations, respectively, by randomly assigning 10 healthy subjects to two periods of 24 trainings sessions over 8 weeks in a cross-over design, separated by 12 weeks of detraining. Maximal oxygen uptake (VO2max), cardiac output (Qmax) and maximal arteriovenous oxygen difference (Da-vO2max) were obtained during an exhaustive incremental test before and after each training period. VO2max and Qmax increased only after IT (from 26.3 +/- 1.6 to 35.2 +/- 3.8 ml min(-1) kg(-1) and from 17.5 +/- 1.3 to 19.5 +/- 1.8 l min(-1), respectively; P < 0.01). Da-vO2max increased after both protocols (from 11.0 +/- 0.8 to 12.7 +/- 1.0; P < 0.01 and from 11.0 +/- 0.8 to 12.1 +/- 1.0 ml 100 ml(-1), P < 0.05 in CT and IT, respectively). At submaximal intensity a significant rightward shift of the Q/Da-vO2 relationship appeared only after CT. These results suggest that in isoenergetic training, central and peripheral adaptations in oxygen transport and utilization are training-modality dependant. IT improves both central and peripheral components of Da-vO2max whereas CT is mainly associated with greater oxygen extraction.

Key points• Mitochondria are increasingly implicated in the pathogenesis of Duchenne muscular dystrophy (DMD). However, the extent to which the multiple facets of mitochondrial function are altered remains uncertain due to the lack of detailed assessment.• Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) was recently shown to improve muscle pathology in dystrophic muscle. However, the mechanisms are not fully elucidated.• This study provides novel information on mitochondrial dysfunction in DMD namely that (i) loss of mitochondrial biomass precedes overt respiratory abnormalities, (ii) mitochondrial H 2 O 2 metabolism is improved at a time when no oxidative damage is detectable in the muscle, and (iii) susceptibility to permeability transition pore (PTP) opening is increased, which has only been inferred in the past, but never actually measured.• This study also provides new mechanistic information regarding the beneficial effects of PGC1α overexpression upon dystrophic muscles, namely that PGC1α not only increases mitochondrial biomass but also reduces PTP opening, improves mitochondrial Ca 2+ handling and reduces the activation of Ca 2+ and mitochondria-dependent proteases in muscles of mdx mice. These mechanisms were not examined in previous investigations, which had largely attributed the improved histopathology after PGC1α therapy to utrophin upregulation.Abstract Alterations of mitochondrial function have been implicated in the pathogenesis of Duchenne muscular dystrophy. In the present study, mitochondrial respiratory function, reactive oxygen species (ROS) dynamics and susceptibility to Ca 2+ -induced permeability transition pore (PTP) opening were investigated in permeabilized skeletal muscle fibres of 6-week-old mdx mice, in order to characterize the magnitude and nature of mitochondrial dysfunction at an early post-necrotic stage of the disease. Short-term overexpression of the transcriptional co-activator PGC1α, achieved by in vivo plasmid transfection, was then performed to determine whether this intervention could prevent mitochondrial impairment and mitigate associated biochemical abnormalities. Compared with normal mice, mdx mice exhibited a lower mitochondrial biomass and oxidative capacity, greater ROS buffering capabilities, and an increased vulnerability to Ca 2+ -induced opening of the mitochondrial permeability transition pore complex. PGC1α gene transfer restored mitochondrial biomass, normalized the susceptibility to PTP opening and R. Godin and F. Daussin are co-first authors. B. J. Petrof and Y. Burelle are co-senior authors.

During transition from rest to exercise, metabolic reaction rates increase substantially to sustain intracellular ATP use. These metabolic demands activate several kinases that initiate signal transduction pathways which modulate transcriptional regulation of mitochondrial biogenesis. The purpose of this study was to determine whether metabolic fluctuations per se affect the signaling cascades known to regulate peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α). On two separate occasions, nine men performed a continuous (30-min) and an intermittent exercise (30 × 1-min intervals separated by 1-min of recovery) at 70% of . Skeletal muscle biopsies from the vastus lateralis were taken at rest and at +0 h and +3 h after each exercise. Metabolic fluctuations that correspond to exercise-induced variation in metabolic rates were determined by analysis of VO2 responses. During intermittent exercise metabolic fluctuations were 2.8-fold higher despite identical total work done to continuous exercise (317 ± 41 vs. 312 ± 56 kJ after intermittent and continuous exercise, respectively). Increased phosphorylation of AMP-activated protein kinase (AMPK) (˜2.9-fold, P < 0.01), calcium/calmodulin-dependent protein kinase II (CaMKII) (˜2.7-fold, P < 0.01) and p38-mitogen-activated protein kinase (MAPK) (˜4.2-fold, P < 0.01) occurred immediately in both exercises and to a greater extent after the intermittent exercise (condition x time interaction, P < 0.05). A single bout of intermittent exercise induces a greater activation of these signaling pathways regulating PGC-1α when compared to a single bout of continuous exercise of matched work and intensity. Chronic adaptations to exercise on mitochondria biogenesis are yet to be investigated.

This study explored mitochondrial capacities to oxidize carbohydrate and fatty acids and functional optimization of mitochondrial respiratory chain complexes in athletes who regularly train at high exercise intensity (ATH, n = 7) compared with sedentary (SED, n = 7). Peak O(2) uptake (Vo(2max)) was measured, and muscle biopsies of vastus lateralis were collected. Maximal O(2) uptake of saponin-skinned myofibers was evaluated with several metabolic substrates [glutamate-malate (V(GM)), pyruvate (V(Pyr)), palmitoyl carnitine (V(PC))], and the activity of the mitochondrial respiratory complexes II and IV were assessed using succinate (V(s)) and N,N,N',N'-tetramethyl-p-phenylenediamine dihydrochloride (V(TMPD)), respectively. Vo(2max) was higher in ATH than in SED (57.8 +/- 2.2 vs. 31.4 +/- 1.3 ml.min(-1).kg(-1), P < 0.001). V(GM) was higher in ATH than in SED (8.6 +/- 0.5 vs. 3.3 +/- 0.3 micromol O(2).min(-1).g dry wt(-1), P < 0.001). V(Pyr) was higher in ATH than in SED (8.7 +/- 1.0 vs. 5.5 +/- 0.2 micromol O(2).min(-1).g dry wt(-1), P < 0.05), whereas V(PC) was not significantly different (5.3 +/- 0.9 vs. 4.4 +/- 0.5 micromol O(2).min(-1).g dry wt(-1)). V(S) was higher in ATH than in SED (11.0 +/- 0.6 vs. 6.0 +/- 0.3 micromol O(2).min(-1).g dry wt(-1), P < 0.001), as well as V(TMPD) (20.1 +/- 1.0 vs. 16.2 +/- 3.4 micromol O(2).min(-1).g dry wt(-1), P < 0.05). The ratios V(S)/V(GM) (1.3 +/- 0.1 vs. 2.0 +/- 0.1, P < 0.001) and V(TMPD)/V(GM) (2.4 +/- 1.0 vs. 5.2 +/- 1.8, P < 0.01) were lower in ATH than in SED. In conclusion, comparison of ATH vs. SED subjects suggests that regular endurance training at high intensity promotes the enhancement of maximal mitochondrial capacities to oxidize carbohydrate rather than fatty acid and induce specific adaptations of the mitochondrial respiratory chain at the level of complex I.