title: PPARdelta agonism inhibits skeletal muscle PDC activity, mitochondrial ATP production and force generation during prolonged contraction.
abstract: We have recently shown that PPARdelta agonism, used clinically to treat insulin resistance, increases fat oxidation and up-regulates mitochondrial PDK4 mRNA and protein expression in resting skeletal muscle. We hypothesized that PDK4 up-regulation, which inhibits pyruvate dehydrogenase complex (PDC)-dependent carbohydrate (CHO) oxidation, would negatively affect muscle function during sustained contraction where the demand on CHO is markedly increased. Three groups of eight male Wistar rats each received either vehicle or a PPARdelta agonist (GW610742X) at two doses (5 and 100 mg (kg body mass (bm))(-1) orally for 6 days. On the seventh day, the gastrocnemius-soleus-plantaris muscle group was isolated and snap frozen, or underwent 30 min of electrically evoked submaximal intensity isometric contraction using a perfused hindlimb model. During contraction, the rate of muscle PDC activation was significantly lower at 100 mg (kg bm)(-1) compared with control (P < 0.01). Furthermore, the rates of muscle PCr hydrolysis and lactate accumulation were significantly increased at 100 mg (kg bm)(-1) compared with control, reflecting lower mitochondrial ATP generation. Muscle tension development during contraction was significantly lower at 100 mg (kg bm)(-1) compared with control (25%; P < 0.05). The present data demonstrate that PPARdelta agonism inhibits muscle CHO oxidation at the level of PDC during prolonged contraction, and is paralleled by the activation of anaerobic metabolism, which collectively impair contractile function.
authors.affiliation: Centre for Integrated Systems Biology and Medicine, Queens Medical Centre, University of Nottingham Medical School, Nottingham NG7 2UH, UK. tim.constantin@nottingham.ac.uk.
authors.forename: Dumitru
authors.initials: D
authors.lastname: Constantin-Teodosiu
authors.forename: David J
authors.initials: DJ
authors.lastname: Baker
authors.forename: Despina
authors.initials: D
authors.lastname: Constantin
authors.forename: Paul L
authors.initials: PL
authors.lastname: Greenhaff
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000818:Animals; D050260:Carbohydrate Metabolism / Q000187:drug effects; D004558:Electric Stimulation; D005947:Glucose / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology*; D010084:Oxidation-Reduction; D047494:PPAR delta / Q000819:agonists*; D011768:Pyruvate Dehydrogenase Complex / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D013844:Thiazoles / Q000008:administration & dosage
chemical_list: C503394:GW 610742; D047494:PPAR delta; D011768:Pyruvate Dehydrogenase Complex; D013844:Thiazoles; D019344:Lactic Acid; D000255:Adenosine Triphosphate; D005947:Glucose