Selective PPARdelta agonist treatment increases skeletal muscle lipid metabolism without altering mitochondrial energy coupling: an in vivo magnetic resonance spectroscopy study.
Peroxisome proliferator-activated receptor-delta (PPARdelta) 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 PPARdelta stimulation has not been examined. Therefore, in this study we examined the response of a selective PPARdelta 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 (1)H-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 (1)H-MRS experiment (day 8), [1-(13)C]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), (31)P-MRS was used to measure hindlimb ATP synthesis and (13)C-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 PPARdelta-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.
Jucker
Beat M
BM
Cardiovascular and Urogenital Center of Excellence for Drug Discovery, GlaxoSmithKline, UW2510, King of Prussia, PA 19406, USA. beat.m.jucker@gsk.com
Yang
Dewen
D
Casey
Warren M
WM
Olzinski
Alan R
AR
Williams
Carolyn
C
Lenhard
Stephen C
SC
Legos
Jeffrey J
JJ
Hawk
C Terrance
CT
Sarkar
Susanta K
SK
Newsholme
Stephen J
SJ
D000818:Animals; D002784:Cholesterol / Q000097:blood; D002952:Citric Acid Cycle / Q000187:drug effects; D005230:Fatty Acids, Nonesterified / Q000097:blood; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D054833:Isoindoles / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010084:Oxidation-Reduction; D047494:PPAR delta / Q000819:agonists* / Q000494:pharmacology; D012313:RNA / Q000737:chemistry / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood
D005230:Fatty Acids, Nonesterified; D051275:Glucose Transporter Type 4; D054833:Isoindoles; C515270:N-(2-(4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo(f)isoindol-2-yl)phenyl)acetyl)benzene sulphonamide; D047494:PPAR delta; C495694:Slc2a4 protein, rat; D013449:Sulfonamides; D014280:Triglycerides; D012313:RNA; D002784:Cholesterol; D005947:Glucose