title: Mitochondrial uncoupling reduces exercise capacity despite several skeletal muscle metabolic adaptations.
abstract: The effects of mitochondrial uncoupling on skeletal muscle mitochondrial adaptation and maximal exercise capacity are unknown. In this study, rats were divided into a control group (CTL, n = 8) and a group treated with 2,4-dinitrophenol, a mitochondrial uncoupler, for 28 days (DNP, 30 mg·kg(-1)·day(-1) in drinking water, n = 8). The DNP group had a significantly lower body mass (P < 0.05) and a higher resting oxygen uptake (Vo2, P < 0.005). The incremental treadmill test showed that maximal running speed and running economy (P < 0.01) were impaired but that maximal Vo2 (Vo2max) was higher in the DNP-treated rats (P < 0.05). In skinned gastrocnemius fibers, basal respiration (V0) was higher (P < 0.01) in the DNP-treated animals, whereas the acceptor control ratio (ACR, Vmax/V0) was significantly lower (P < 0.05), indicating a reduction in OXPHOS efficiency. In skeletal muscle, DNP activated the mitochondrial biogenesis pathway, as indicated by changes in the mRNA expression of PGC1-α and -β, NRF-1 and -2, and TFAM, and increased the mRNA expression of cytochrome oxidase 1 (P < 0.01). The expression of two mitochondrial proteins (prohibitin and Ndufs 3) was higher after DNP treatment. Mitochondrial fission 1 protein (Fis-1) was increased in the DNP group (P < 0.01), but mitofusin-1 and -2 were unchanged. Histochemical staining for NADH dehydrogenase and succinate dehydrogenase activity in the gastrocnemius muscle revealed an increase in the proportion of oxidative fibers after DNP treatment. Our study shows that mitochondrial uncoupling induces several skeletal muscle adaptations, highlighting the role of mitochondrial coupling as a critical factor for maximal exercise capacities. These results emphasize the importance of investigating the qualitative aspects of mitochondrial function in addition to the amount of mitochondria.
authors: University of Strasbourg, Faculty of Medicine, FMTS, EA 3072, Strasbourg, France;
authors: A I
authors: AI
authors: Schlagowski
authors: F
authors: F
authors: Singh
authors: A L
authors: AL
authors: Charles
authors: T
authors: T
authors: Gali Ramamoorthy
authors: F
authors: F
authors: Favret
authors: F
authors: F
authors: Piquard
authors: B
authors: B
authors: Geny
authors: J
authors: J
authors: Zoll
mesh_terms: D019297:2,4-Dinitrophenol / Q000494:pharmacology*; D000222:Adaptation, Physiological; D000818:Animals; D002460:Cell Line; D004734:Energy Metabolism / Q000187:drug effects*; D017079:Exercise Tolerance / Q000187:drug effects*; D005786:Gene Expression Regulation; D007700:Kinetics; D008297:Male; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D063269:Mitochondrial Turnover / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D005082:Physical Exertion; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012420:Running; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014475:Uncoupling Agents / Q000494:pharmacology*
chemical_list: D024101:Mitochondrial Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D012333:RNA, Messenger; C489030:Tfam protein, rat; D014157:Transcription Factors; D014475:Uncoupling Agents; D019297:2,4-Dinitrophenol
keywords: 2,4-dinitrophenol; exhaustive exercise; gas exchanges; maximal oxygen uptake; maximal running speed; mitochondrial uncoupling