Reduced PGC-1α expression is associated with reduced respiratory capacity and substrate switching in unloaded rat heart

Aims: The transcriptional coactivator PGC-1α is induced by increased energy demand, regulates fatty acid oxidation, and has been suggested to coordinate energy substrate preference in skeletal muscle. PGC-1α also regulates respiratory capacity and is abundantly expressed in heart muscle.

Objective: To investigate the regulation of myocardial respiratory capacity in response to decreased energy demand and assess substrate oxidation patterns in the isolated working rat heart.

Methods and results: Energy demand was chronically reduced by unloading the left ventricle through heterotopic rat heart transplantation (atrophy). Atrophied working hearts demonstrated reduced contractile function and a switch from fatty acid oxidation (FAO) to glucose oxidation (GO +88%; FAO –51%). State 3 respiration of isolated mitochondria was markedly decreased, both with glutamate and succinate as a substrate (natomsO/min/mg: glutamate 85±27 vs. 224±32, p<0.01; succinate 59±18 vs. 154±30, p<0.05). We also observed reduced expression of respiratory chain mRNA (complex I –49%, p<0.05; complex II –61%, p<0.001) and protein (complex I –42%, p<0.01; complex II –57%, p<0.05; complex IV –65%, p<0.05). Lastly, the expression of PGC-1α was significantly decreased (–55%, p<0.05). No changes were observed in the expression of NRF-1, NRF-2, TFAm, ERRα and PGC-1β.

Conclusions: Reduced expression of PGC-1α correlates with reduced respiratory chain gene expression and function and is also associated with a switch in energy substrate preference in isolated working atrophied hearts. We suggest that the decreased expression of PGC-1α may regulate respiratory capacity and contribute to the switch in substrate preference in response to decreased energy demands.