PMID- 19001043
OWN - NLM
STAT- MEDLINE
DCOM- 20090318
LR  - 20211020
IS  - 1469-7793 (Electronic)
IS  - 0022-3751 (Print)
IS  - 0022-3751 (Linking)
VI  - 587
IP  - 1
DP  - 2009 Jan 15
TI  - PPARdelta agonism inhibits skeletal muscle PDC activity, mitochondrial ATP 
      production and force generation during prolonged contraction.
PG  - 231-9
LID - 10.1113/jphysiol.2008.164210 [doi]
AB  - 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.
FAU - Constantin-Teodosiu, Dumitru
AU  - Constantin-Teodosiu D
AD  - Centre for Integrated Systems Biology and Medicine, Queens Medical Centre, 
      University of Nottingham Medical School, Nottingham NG7 2UH, UK. 
      tim.constantin@nottingham.ac.uk.
FAU - Baker, David J
AU  - Baker DJ
FAU - Constantin, Despina
AU  - Constantin D
FAU - Greenhaff, Paul L
AU  - Greenhaff PL
LA  - eng
PT  - Journal Article
DEP - 20081110
PL  - England
TA  - J Physiol
JT  - The Journal of physiology
JID - 0266262
RN  - 0 (GW 610742)
RN  - 0 (PPAR delta)
RN  - 0 (Pyruvate Dehydrogenase Complex)
RN  - 0 (Thiazoles)
RN  - 33X04XA5AT (Lactic Acid)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Adenosine Triphosphate/*biosynthesis
MH  - Animals
MH  - Carbohydrate Metabolism/drug effects
MH  - Electric Stimulation
MH  - Glucose/metabolism
MH  - Lactic Acid/metabolism
MH  - Male
MH  - Mitochondria, Muscle/drug effects/metabolism
MH  - Muscle Contraction/drug effects/*physiology
MH  - Muscle, Skeletal/drug effects/*physiology
MH  - Oxidation-Reduction
MH  - PPAR delta/*agonists
MH  - Pyruvate Dehydrogenase Complex/*antagonists & inhibitors
MH  - Rats
MH  - Rats, Wistar
MH  - Thiazoles/administration & dosage
PMC - PMC2670036
EDAT- 2008/11/13 09:00
MHDA- 2009/03/19 09:00
PMCR- 2010/01/01
CRDT- 2008/11/13 09:00
PHST- 2008/11/13 09:00 [pubmed]
PHST- 2009/03/19 09:00 [medline]
PHST- 2008/11/13 09:00 [entrez]
PHST- 2010/01/01 00:00 [pmc-release]
AID - jphysiol.2008.164210 [pii]
AID - 10.1113/jphysiol.2008.164210 [doi]
PST - ppublish
SO  - J Physiol. 2009 Jan 15;587(1):231-9. doi: 10.1113/jphysiol.2008.164210. Epub 2008 
      Nov 10.