Peroxisome proliferator-activated receptor γ coactivator 1β (PGC-1β) improves skeletal muscle mitochondrial function and insulin sensitivity
Proteins belonging to the peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1) family are key regulators of cellular energy homeostasis in a number of oxidative tissues, including skeletal muscle. While the regulation and function of PGC-1α seems central to muscle fibre plasticity in endurance exercise, the role of PGC-1β in this tissue is less clear. Wright et al. (Diabetologia, DOI: 10.1007/s00125-011-2068-x) provide evidence for a protective effect of moderately elevated PGC-1β in electroporated rat skeletal muscle against high-fat-diet-induced insulin resistance, at least in part by promoting the oxidation of long chain acyl-CoA entities and the elimination of reactive oxygen species. These data provide important insights into the biological role of PGC-1β in skeletal muscle and imply novel therapeutic avenues for improving peripheral insulin sensitivity.
KeywordsInsulin resistance Long-chain acyl-CoA PGC-1β Reactive oxygen species Skeletal muscle
Peroxisome proliferator-activated receptor γ coactivator
Dysregulation of PGC-1α and PGC-1β gene expression levels has been found in the skeletal muscle of type 2 diabetic patients and individuals with impaired glucose tolerance, at least in some populations [6, 7]. Studies in skeletal muscle-specific knockout mice for Pgc-1α or Pgc-1β alone failed to show a direct involvement of genetic ablation of the individual coactivators in the aetiology of insulin resistance in this tissue [8, 9, 10]. The consequence of a Pgc-1α/Pgc-1β muscle-specific double knockout approach remains unknown. In contrast, the data provided by Wright et al.  suggest a protective role for PGC-1β against high-fat-diet-induced insulin resistance in skeletal muscle. Similarly, the moderate and acute modulation of electroporated PGC-1α in muscle resulted in improvement of insulin sensitivity in the muscle of lean and obese Zucker rats . Interestingly, the exact opposite observation, i.e. a more rapidly progressing insulin resistance, was reported for high-fat-fed muscle-specific Pgc-1α transgenic mice . The electroporation-based approach used by Wright et al.  to increase PGC-1β levels in individual muscles differs from the use of muscle-specific transgenic animals, which produces a stronger, chronic elevation of PGC-1β . Thus, potentially confounding effects caused by the strong transgenic expression—such as the strong inhibition of Pgc-1α gene expression in the Pgc-1β muscle-specific transgenic animals  that could contribute to the muscle fibre-type switch observed in these mice—were not encountered by Wright et al. Taking into consideration their findings and the previous work by Bonen et al. , Wright et al. propose that a moderate acute elevation of PGC-1α or PGC-1β restores insulin sensitivity, at least in glycolytic muscles in rats. Accordingly, modulation of PGC-1α and PGC-1β gene expression might be an attractive novel therapeutic option against type 2 diabetes. However, designing pharmacological interventions aimed at the PGC-1 coactivators is not a trivial task . First, the chemical entities that selectively induce PGC-1α or PGC-1β gene expression in skeletal muscle remain elusive. Second, pharmacological methods that alter PGC-1 levels must achieve a concentration within a therapeutically beneficial window in order to avoid the detrimental effects associated with inadequate or excessive PGC-1 levels . Finally, some paradoxical findings about the PGC-1 coactivators in muscle remain unexplained. For example, in the present study , Pgc-1β expression and oxidative metabolism are already increased as a consequence of the high-fat diet, and it is unclear how further elevation of PGC-1β levels exerts the observed amelioration of insulin sensitivity. Moreover, while ectopic PGC-1β lowers the long-chain acyl-CoA pool in muscle, the high-fat-diet-induced elevation of intramuscular ceramide and diacylglycerol, both strongly implicated in causing insulin resistance , is unaffected. It is also unclear how the chronic vs acute and moderate vs strong expression of Pgc-1α and Pgc-1β differ mechanistically and, at least in the case of Pgc-1α, result in diametrically opposite outcomes in terms of peripheral insulin sensitivity. Whether this is also true for Pgc-1β is unclear, since the effect of the transgenic expression of Pgc-1β in muscle on insulin resistance has not yet been elucidated . Therefore, more studies are needed to fundamentally understand the regulation and function of the PGC-1 proteins in skeletal muscle before an appropriate drug-targeting strategy aimed at these coactivators can be attempted.
The research in our laboratory is supported by the Swiss National Science Foundation (SNF), the Muscular Dystrophy Association USA (MDA), the Association Française contre les Myopathies (AFM), the Swiss Society for Research on Muscle Diseases (SSEM), the Gebert-Rüf Foundation ‘Rare Diseases’ Program (GRS), the Swiss Initiative in Systems Biology (SystemsX.ch), the United Mitochondrial Disease Foundation (UMDF), the Roche Foundation, the Swiss Diabetes Association, the SwissLife ‘Jubiläumsstiftung für Volksgesundheit und medizinische Forschung’ and the University of Basel.
Duality of interest statement
The author declares that there is no duality of interest associated with this manuscript.
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