The role of PGC-1α in the regulation of skeletal muscle metabolism

The purpose of this review was to provide an understanding of the role of PGC-1α in the regulation of skeletal muscle metabolism and to describe the results of studies on the association of the polymorphism gene PPARGC1A with human muscle performance.     

PGC-1β regulates angiogenesis in skeletal muscle

Patients who experience acute ischemic stroke may develop hyperglycemia, even in the absence of diabetes, but the exact mechanisms are still unclear. Adipose tissue secretes numerous proinflammatory cytokines and is involved in the regulation of glucose metabolism. This study aimed to determine the effects of acute stroke on adipose inflammatory cytokine expression. In addition, because sympathetic activity is activated after acute stroke and catecholamines can regulate the expression of several adipocytokines, this study also evaluated whether alterations in adipose proinflammatory cytokines following acute stroke, if any, were medicated by sympathetic system. Acute ischemic brain injury was induced by ligating the right middle cerebral artery and bilateral common carotid arteries in male adult Sprague-Dawley rats. Adipose tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) mRNA and protein levels were determined by RT-PCR and enzyme-linked immunoassay, respectively. The stroke rats developed glucose intolerance on days 1 and 2 after cerebral ischemic injury. The fasting blood insulin levels and insulin resistance index measured by homeostasis model assessment were higher in the stroke rats compared with the sham group. Epididymal adipose TNF-α and MCP-1 mRNA and protein levels were elevated one- to twofold, in association with increased macrophage infiltration into the adipose tissue. When the rats were treated with a nonselective β-adrenergic receptor blocker, propranolol, before induction of cerebral ischemic injury, the acute stroke-induced increase in TNF-α and MCP-1 was blocked, and fasting blood insulin concentration and homeostasis model assessment-insulin resistance were decreased. These results suggest a potential role of adipose proinflammatory cytokines induced by the sympathetic nervous system in the pathogenesis of glucose metabolic disorder in rats with acute ischemic stroke.     

Modular Evolution of PGC-1α in Vertebrates

In mammals, the peroxisome proliferator activated receptor (PPAR)γ coactivator-1α (PGC-1α) is a central regulator of mitochondrial gene expression, acting in concert with nuclear respiratory factor-1 (NRF-1) and the PPARs. Its role as a “master regulator” of oxidative capacity is clear in mammals, but its role in other vertebrates is ambiguous. In lower vertebrates, although PGC-1α seems to play a role in coordinating the PPARα axis as in mammals, it does not appear to be involved in NRF-1 regulation of mitochondrial content. To evaluate the evolutionary patterns of this coactivator in fish and mammals, we investigated the evolutionary trajectories of PGC-1α homologs in representative vertebrate lineages. A phylogeny of the PGC-1 paralogs suggested that the family diversified through repeated genome duplication events early in vertebrate evolution. Bayesian and maximum likelihood phylogenetic reconstructions of PGC-1α in representative vertebrate species revealed divergent evolutionary dynamics across the different functional domains of the protein. Specifically, PGC-1α exhibited strong conservation of the activation/PPAR interaction domain across vertebrates, whereas the NRF-1 and MEF2c interaction domains experienced accelerated rates of evolution in actinopterygian (fish lineages) compared to sarcopterygians (tetrapod lineages). Furthermore, analysis of the amino acid sequence of these variable domains revealed successive serine- and glutamine-rich insertions within the teleost lineages, with important ramifications for PGC-1α function in these lineages. Collectively, these results suggest modular evolution of the PGC-1α protein in vertebrates that could allow for lineage-specific divergences in the coactivating capabilities of this regulator.     

Endothelial PGC-1α Mediates Vascular Dysfunction in Diabetes

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Role of PGC-1α in Mitochondrial Quality Control in Neurodegenerative Diseases

Neurochemical Research - As one of the major cell organelles responsible for ATP production, it is important that neurons maintain mitochondria with structural and functional integrity; this is...     

Inverse Regulation of the Cytosolic Ca2+ Buffer Parvalbumin and Mitochondrial Volume in Muscle Cells via SIRT1/PGC-1α Axis

Skeletal muscles show a high plasticity to cope with various physiological demands. Different muscle types can be distinguished by the force, endurance, contraction/relaxation kinetics (fast-twitch vs. slow-twitch muscles), oxidative/glycolytic capacity, and also with respect to Ca²⁺-signaling components. Changes in Ca²⁺ signaling and associated Ca²⁺-dependent processes are thought to underlie the high adaptive capacity of muscle fibers. Here we investigated the consequences and the involved mechanisms caused by the ectopic expression of the Ca²⁺-binding protein parvalbumin (PV) in C2C12 myotubes in vitro, and conversely, the effects caused by its absence in in fast-twitch muscles of parvalbumin null-mutant (PV−/−) mice in vivo. The absence of PV in fast-twitch muscle tibialis anterior (TA) resulted in an increase in the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and of its positive regulator, the deacetylase sirtuin 1 (SIRT1). TA muscles from PV−/− mice also have an increased mitochondrial volume. Mild ionophore treatment of control (PV-devoid) C2C12 myotubes causing a moderate elevation in [Ca²⁺]_c resulted in an increase in mitochondrial volume, together with elevated PGC-1α and SIRT1 expression levels, whilst it increased PV expression levels in myotubes stably transfected with PV. In PV-expressing myotubes the mitochondrial volume, PGC-1α and SIRT1 were significantly lower than in control C2C12 myotubes already at basal conditions and application of ionophore had no effect on either one. SIRT1 activation causes a down-regulation of PV in transfected myotubes, whilst SIRT1 inhibition has the opposite effect. We conclude that PV expression and mitochondrial volume in muscle cells are inversely regulated via a SIRT1/PGC-1α signaling axis.     

Muscling in on PGC-1α for improved quality of life in ALS

Impaired activity of peroxisome proliferator-activated receptor (PPAR)-γ coactivator (PGC)-1α has been implicated in the pathophysiology of several neurodegenerative disorders. In this issue, Da Cruz et al. (2012) show improved muscle function, but not survival, with increased PGC-1α activity in muscle in a mouse model of amyotrophic lateral sclerosis.     

PGC-1α determines light damage susceptibility of the murine retina

The peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1) proteins are key regulators of cellular bioenergetics and are accordingly expressed in tissues with a high energetic demand. For example, PGC-1α and PGC-1β control organ function of brown adipose tissue, heart, brain, liver and skeletal muscle. Surprisingly, despite their prominent role in the control of mitochondrial biogenesis and oxidative metabolism, expression and function of the PGC-1 coactivators in the retina, an organ with one of the highest energy demands per tissue weight, are completely unknown. Moreover, the molecular mechanisms that coordinate energy production with repair processes in the damaged retina remain enigmatic. In the present study, we thus investigated the expression and function of the PGC-1 coactivators in the healthy and the damaged retina. We show that PGC-1α and PGC-1β are found at high levels in different structures of the mouse retina, most prominently in the photoreceptors. Furthermore, PGC-1α knockout mice suffer from a striking deterioration in retinal morphology and function upon detrimental light exposure. Gene expression studies revealed dysregulation of all major pathways involved in retinal damage and apoptosis, repair and renewal in the PGC-1α knockouts. The light-induced increase in apoptosis in vivo in the absence of PGC-1α was substantiated in vitro, where overexpression of PGC-1α evoked strong anti-apoptotic effects. Finally, we found that retinal levels of PGC-1 expression are reduced in different mouse models for retinitis pigmentosa. We demonstrate that PGC-1α is a central coordinator of energy production and, importantly, all of the major processes involved in retinal damage and subsequent repair. Together with the observed dysregulation of PGC-1α and PGC-1β in retinitis pigmentosa mouse models, these findings thus imply that PGC-1α might be an attractive target for therapeutic approaches aimed at retinal degeneration diseases.