Selective PPARdelta agonist treatment increases skeletal muscle lipid metabolism without altering mitochondrial energy coupling: an in vivo magnetic resonance spectroscopy study
| Autor: | C. Terrance Hawk, Stephen C. Lenhard, Carolyn Williams, Alan R. Olzinski, Warren M. Casey, Jeffrey J. Legos, Stephen J. Newsholme, Susanta K. Sarkar, Beat M. Jucker, Dewen Yang |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
medicine.medical_specialty
Magnetic Resonance Spectroscopy Physiology Endocrinology Diabetes and Metabolism Citric Acid Cycle Gene Expression Mitochondrion Biology Fatty Acids Nonesterified Isoindoles Creatine Rats Sprague-Dawley chemistry.chemical_compound Physiology (medical) Internal medicine medicine Uncoupling protein Animals Carnitine PPAR delta Muscle Skeletal Beta oxidation Triglycerides Oligonucleotide Array Sequence Analysis Soleus muscle Sulfonamides Glucose Transporter Type 4 Skeletal muscle Lipid metabolism Lipid Metabolism Mitochondria Muscle Rats Endocrinology medicine.anatomical_structure Cholesterol Glucose chemistry RNA Oxidation-Reduction medicine.drug |
| Zdroj: | American journal of physiology. Endocrinology and metabolism. 293(5) |
| ISSN: | 0193-1849 |
| Popis: | Peroxisome proliferator-activated receptor-δ (PPARδ) 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 PPARδ stimulation has not been examined. Therefore, in this study we examined the response of a selective PPARδ 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 (Vtca). There was no alteration, at either dose, in mitochondrial coupling efficiency measured as the ratio of unidirectional ATP synthesis flux to Vtca. 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 PPARδ-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. |
| Databáze: | OpenAIRE |
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