Regulatory role of PGC-1α/PPAR signaling in skeletal muscle metabolic recruitment during cold acclimation.
This study examined the molecular basis of energy-related regulatory mechanisms underlying metabolic recruitment of skeletal muscle during cold acclimation and possible involvement of the l-arginine/nitric oxide-producing pathway. Rats exposed to cold (4±1°C) for periods of 1, 3, 7, 12, 21 and 45 days were divided into three groups: untreated, l-arginine treated and N(ω)-nitro-l-arginine methyl ester (l-NAME) treated. Compared with controls (22±1°C), there was an initial increase in the protein level of 5'-AMP-activated protein kinase α (day 1), followed by an increase in peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and peroxisome proliferator-activated receptors (PPARs): PPARα and PPARγ from day 1 and PPARδ from day 7 of cold acclimation. Activation of the PGC-1α/PPAR transcription program was accompanied by increased protein expression of the key metabolic enzymes in β-oxidation, the tricarboxylic acid cycle and oxidative phosphorylation, with the exceptions in complex I (no changes) and ATP synthase (decreased at day 1). Cold did not affect hexokinase and GAPDH protein levels, but increased lactate dehydrogenase activity compared with controls (1-45 days). l-arginine sustained, accelerated and/or intensified cold-induced molecular remodeling throughout cold acclimation. l-NAME exerted phase-dependent effects: similar to l-arginine in early cold acclimation and opposite after prolonged cold exposure (from day 21). It seems that upregulation of the PGC-1α/PPAR transcription program early during cold acclimation triggers the molecular recruitment of skeletal muscle underlying the shift to more oxidative metabolism during prolonged cold acclimation. Our results suggest that nitric oxide has a role in maintaining the skeletal muscle oxidative phenotype in late cold acclimation but question its role early in cold acclimation.
University of Belgrade, Department of Physiology, Institute for Biological Research 'Sinisa Stankovic', Bulevar despota Stefana 142, 11060 Belgrade, Serbia.
Ana
A
Stancic
Biljana
B
Buzadzic
Aleksandra
A
Korac
Vesna
V
Otasevic
Aleksandra
A
Jankovic
Milica
M
Vucetic
Milica
M
Markelic
Ksenija
K
Velickovic
Igor
I
Golic
Bato
B
Korac
D000064:Acclimatization / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D015153:Blotting, Western; D016022:Case-Control Studies; D003080:Cold Temperature; D004591:Electrophoresis, Polyacrylamide Gel; D005786:Gene Expression Regulation / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*
D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D014157:Transcription Factors; D009569:Nitric Oxide; D001120:Arginine; D019331:NG-Nitroarginine Methyl Ester
cold acclimation; metabolism; skeletal muscle; transcription control