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This Article Full Text Full Text (PDF) All Versions of this Article: 297/1/C217    most recent 00070.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Adhihetty, P. J. Articles by Hood, D. A. PubMed PubMed Citation Articles by Adhihetty, P. J. Articles by Hood, D. A.

CELLULAR AND MITOCHONDRIAL METABOLISM

The role of PGC-1 on mitochondrial function and apoptotic susceptibility in muscle

¹School of Kinesiology and Health Science, ²Department of Biology, and ³The Muscle Health Research Centre, York University, Toronto, Ontario, Canada; ⁴Copenhagen Muscle Research Centre and Centre of Inflammation and Metabolism, Department of Biology, University of Copenhagen, Denmark, and ⁵Institute of Neurosciences and Department of Cellular Biology, Physiology and Immunology, Autonomous University of Barcelona, Barcelona, Spain

Submitted 12 February 2009 ; accepted in final form 5 May 2009

Mitochondria are critical for cellular bioenergetics, and they mediate apoptosis within cells. We used whole body peroxisome proliferator-activated receptor- coactivator-1 (PGC-1) knockout (KO) animals to investigate its role on organelle function, apoptotic signaling, and cytochrome-c oxidase activity, an indicator of mitochondrial content, in muscle and other tissues (brain, liver, and pancreas). Lack of PGC-1 reduced mitochondrial content in all muscles (17–44%; P < 0.05) but had no effect in brain, liver, and pancreas. However, the tissue expression of proteins involved in mitochondrial DNA maintenance [transcription factor A (Tfam)], import (Tim23), and remodeling [mitofusin 2 (Mfn2) and dynamin-related protein 1 (Drp1)] did not parallel the decrease in mitochondrial content in PGC-1 KO animals. These proteins remained unchanged or were upregulated (P < 0.05) in the highly oxidative heart, indicating a change in mitochondrial composition. A change in muscle organelle composition was also evident from the alterations in subsarcolemmal and intermyofibrillar mitochondrial respiration, which was impaired in the absence of PGC-1. However, endurance-trained KO animals did not exhibit reduced mitochondrial respiration. Mitochondrial reactive oxygen species (ROS) production was not affected by the lack of PGC-1, but subsarcolemmal mitochondria from PGC-1 KO animals released a greater amount of cytochrome c than in WT animals following exogenous ROS treatment. Our results indicate that the lack of PGC-1 results in 1) a muscle type-specific suppression of mitochondrial content that depends on basal oxidative capacity, 2) an alteration in mitochondrial composition, 3) impaired mitochondrial respiratory function that can be improved by training, and 4) a greater basal protein release from subsarcolemmal mitochondria, indicating an enhanced mitochondrial apoptotic susceptibility.

endurance training; exercise; mitochondrial biogenesis; reactive oxygen species