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

Abstract

Mitochondria are critical for cellular bioenergetics, and they mediate apoptosis within cells. We used whole body peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) 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-1alpha 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-1alpha 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-1alpha. 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-1alpha, but subsarcolemmal mitochondria from PGC-1alpha 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-1alpha 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.

Contractile activity-induced mitochondrial biogenesis and mTORC1

“…Furthermore, prolonged mTORC1 inactivation in quiescent myotubes led to the upregulation of certain mitochondrial indicators, although this came at the expense of mitochondrial respiration, reminiscent of cells with mitochondrial disease. This defect could be recovered with the addition of CCA, further fortifying a role for contractile activity in ameliorating mitochondrial dysfunction in muscle (2,21). …”

Muscle oxidative capacity during IL-6-dependent cancer cachexia

“…Reductions in PGC-1␣ are also seen in humans and mice fed a high-fat diet (16,52) and obese mice (16). PGC-1␣ knockout mice have reduced mitochondrial content in white and red muscles, altered mitochondrial function, and increased susceptibility to apoptosis (2). Further work is needed to determine whether PGC-1␣ expression is a critical regulatory event for wasting of glycolytic and oxidative skeletal muscle.…”

Dysfunction of the PGC-1α-mitochondria axis confers adriamycin-induced podocyte injury

“…Therefore, PGC-1␣ can regulate mitochondrial biogenesis. PGC-1␣ loss impairs mitochondrial respiratory function and enhances mitochondrial oxidative stress and apoptotic susceptibility (2,25,40). Haemmerle et al (15) reported that the PGC-1␣ signaling pathway is a potential therapeutic target for the treatment of patients with neutral lipid storage disease.…”