Abstract
The effects of exercise on skeletal muscle are mediated by a coupling between muscle electrical activity and gene expression. Several activity correlates, such as intracellular Ca(2+), hypoxia and metabolites like free fatty acids (FFAs), might initiate signalling pathways regulating fibre-type-specific genes. FFAs can be sensed by lipid-dependent transcription factors of the peroxisome proliferator-activated receptor (PPAR) family. We found that the mRNA for the predominant muscle isoform, PPARdelta, was three-fold higher in the slow/oxidative soleus compared to the fast/glycolytic extensor digitorum longus (EDL) muscle. In histological sections of the soleus, the most oxidative fibres display the highest levels of PPARdelta protein. When the soleus muscle was stimulated electrically by a pattern mimicking fast/glycolytic IIb motor units, the mRNA level of PPARdelta was reduced to less than half within 24 h. In the EDL, a three-fold increase was observed after slow type I-like electrical stimulation. When a constitutively active form of PPARdelta was overexpressed for 14 days in normally active adult fibres after somatic gene transfer, the number of I/IIa hybrids in the EDL more than tripled, IIa fibres increased from 14% to 25%, and IIb fibres decreased from 55% to 45%. The level of succinate dehydrogenase activity increased and size decreased, also when compared to normal fibres of the same type. Thus PPARdelta can change myosin heavy chain, oxidative enzymes and size locally in muscle cells in the absence of general exercise. Previous studies on PPARdelta in muscle have been performed in transgenic animals where the transgene has been present during muscle development. Our data suggest that PPARdelta can mediate activity effects acutely in pre-existing adult fibres, and thus is an important link in excitation-transcription coupling.