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This Article Full Text Full Text (PDF) All Versions of this Article: 293/5/E1256    most recent 00218.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Jucker, B. M. Articles by Newsholme, S. J. Search for Related Content PubMed PubMed Citation Articles by Jucker, B. M. Articles by Newsholme, S. J.

Selective PPAR agonist treatment increases skeletal muscle lipid metabolism without altering mitochondrial energy coupling: an in vivo magnetic resonance spectroscopy study

¹Cardiovascular and Urogenital Center of Excellence for Drug Discovery, ²Laboratory of Animal Sciences, ³High Throughput Biology, ⁴Pre-Clinical Development, and ⁵Technology Development, GlaxoSmithKline, King of Prussia, Pennsylvania

Submitted 7 April 2007 ; accepted in final form 15 August 2007

Peroxisome proliferator-activated receptor- (PPAR) activation results in upregulation of genes associated with skeletal muscle fatty acid oxidation and mitochondrial uncoupling. However, direct, noninvasive assessment of lipid metabolism and mitochondrial energy coupling in skeletal muscle following PPAR stimulation has not been examined. Therefore, in this study we examined the response of a selective PPAR agonist (GW610742X at 5 or 100 mg·kg^–1·day^–1 for 8 days) on skeletal-muscle lipid metabolism and mitochondrial coupling efficiency in rats by using in vivo magnetic resonance spectroscopy (MRS). There was a decrease in the intramyocellular lipid-to-total creatine ratio as assessed by in vivo ¹H-MRS in soleus and tibialis anterior muscles by day 7 (reduced by 49 and 46%, respectively; P < 0.01) at the high dose. Following the ¹H-MRS experiment (day 8), [1-¹³C]glucose was administered to conscious rats to assess metabolism in the soleus muscle. The relative fat-vs.-carbohydrate oxidation rate increased in a dose-dependent manner (increased by 52 and 93% in the 5 and 100 mg·kg^–1·day^–1 groups, respectively; P < 0.05). In separate experiments where mitochondrial coupling was assessed in vivo (day 7), ³¹P-MRS was used to measure hindlimb ATP synthesis and ¹³C-MRS was used to measure the hindlimb tricarboxylic acid cycle flux (V_tca). There was no alteration, at either dose, in mitochondrial coupling efficiency measured as the ratio of unidirectional ATP synthesis flux to V_tca. Soleus muscle GLUT4 expression was decreased by twofold, whereas pyruvate dehydrogenase kinase 4, carnitine palmitoyl transferase 1a, and uncoupling protein 2 and 3 expression was increased by two- to threefold at the high dose (P < 0.05). In summary, these are the first noninvasive measurements illustrating a selective PPAR-mediated decrease in muscle lipid content that was consistent with a shift in metabolic substrate utilization from carbohydrate to lipid. However, the mitochondrial-energy coupling efficiency was not altered in the presence of increased uncoupling protein expression.

peroxisome proliferator-activated receptor-; intramyocellular lipid; mitochondrial coupling; muscle

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