PGC-1a in muscle links metabolism to inflammation

1. In higher eukaryotes, metabolism and immunity are tightly coupled. However, whereas in evolutionary terms, a compromised immune response due to undernourishment has been the predominant problem, the inflammatory response to obesity and other life style-associated diseases has increased in relevance in Western societies in the last hundred years. 2. Traditionally, fat tissue has been considered as the major source of pro-inflammatory secreted factors in these pathologies. In recent years however, the contribution of other tissues to a disease-causing chronic inflammation has been increasingly appreciated. 3. The peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is one of the key regulatory factors in the active skeletal muscle. Aberrant expression of PGC-1α in inactive muscle fibres could link a sedentary life style, persistent systemic inflammation and the higher risk for many chronic diseases. Modulation of PGC-1α activity in skeletal muscle might accordingly have a broad therapeutic effect. Here, recent advances in the understanding of the role of muscle PGC-1α in health and disease are reviewed

Estrogen-related receptor α (ERRα) : a novel target in type 2 diabetes

Recent studies have shown that reduced mitochondrial content and function in skeletal muscle are common features of type 2 diabetes. Here, we review the molecular mechanisms involved in the regulation of mitochondrial genes in skeletal muscle, focusing on a key transcriptional network consisting of ERRα and PGC-1α. We describe how knowledge of this transcriptional circuit can be translated to the development of novel therapies for type 2 diabetes

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 sensitivit

Coordinated balancing of muscle oxidative metabolism through PGC-1α increases metabolic flexibility and preserves insulin sensitivity

The peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) enhances oxidative metabolism in skeletal muscle. Excessive lipid oxidation and electron transport chain activity can, however, lead to the accumulation of harmful metabolites and impair glucose homeostasis. Here, we investigated the effect of over-expression of PGC-1α on metabolic control and generation of insulin desensitizing agents in extensor digitorum longus (EDL), a muscle that exhibits low levels of PGC-1α in the untrained state and minimally relies on oxidative metabolism. We demonstrate that PGC-1α induces a strictly balanced substrate oxidation in EDL by concomitantly promoting the transcription of activators and inhibitors of lipid oxidation. Moreover, we show that PGC-1α enhances the potential to uncouple oxidative phosphorylation. Thereby, PGC-1α boosts elevated, yet tightly regulated oxidative metabolism devoid of side products that are detrimental for glucose homeostasis. Accordingly, PI3K activity, an early phase marker for insulin resistance, is preserved in EDL muscle. Our findings suggest that PGC-1α coordinately coactivates the simultaneous transcription of gene clusters implicated in the positive and negative regulation of oxidative metabolism and thereby increases metabolic flexibility. Thus, in mice fed a normal chow diet, over-expression of PGC-1α does not alter insulin sensitivity and the metabolic adaptations elicited by PGC-1α mimic the beneficial effects of endurance training on muscle metabolism in this context

Point contacts in encapsulated graphene

We present a novel method to establish inner point contacts on hexagonal boron nitride (hBN) encapsulated graphene heterostructures with dimensions as small as 100 nm by pre-patterning the top-hBN in a separate step prior to dry-stacking. 2 and 4-terminal field effect measurements between different lead combinations are in qualitative agreement with an electrostatic model assuming pointlike contacts. The measured contact resistances are 0.5-1.5 k$\Omega$ per contact, which is quite low for such small contacts. By applying a perpendicular magnetic fields, an insulating behaviour in the quantum Hall regime was observed, as expected for inner contacts. The fabricated contacts are compatible with high mobility graphene structures and open up the field for the realization of several electron optical proposals

Suppression of mitochondrial respiration through recruitment of p160 myb binding protein to PGC-1α : modulation by p38 MAPK

The transcriptional coactivator PPAR gamma coactivator 1 α (PGC-1α) is a key regulator of metabolic processes such as mitochondrial biogenesis and respiration in muscle and gluconeogenesis in liver. Reduced levels of PGC-1α in humans have been associated with type II diabetes. PGC-1α contains a negative regulatory domain that attenuates its transcriptional activity. This negative regulation is removed by phosphorylation of PGC-1α by p38 MAPK, an important kinase downstream of cytokine signaling in muscle and β-adrenergic signaling in brown fat. We describe here the identification of p160 myb binding protein (p160MBP) as a repressor of PGC-1α. The binding and repression of PGC-1α by p160MBP is disrupted by p38 MAPK phosphorylation of PGC-1α. Adenoviral expression of p160MBP in myoblasts strongly reduces PGC-1α's ability to stimulate mitochondrial respiration and the expression of the genes of the electron transport system. This repression does not require removal of PGC-1α from chromatin, suggesting that p160MBP is or recruits a direct transcriptional suppressor. Overall, these data indicate that p160MBP is a powerful negative regulator of PGC-1α function and provide a molecular mechanism for the activation of PGC-1α by p38 MAPK. The discovery of p160MBP as a PGC-1α regulator has important implications for the understanding of energy balance and diabetes

The coactivator PGC-1α regulates mouse skeletal muscle oxidative metabolism independently of the nuclear receptor PPARβ/δ in sedentary mice fed a regular chow diet

AIMS/HYPOTHESIS: Physical activity improves oxidative capacity and exerts therapeutic beneficial effects, particularly in the context of metabolic diseases. The peroxisome proliferator-activated receptor (PPAR) γ coactivator-1α (PGC-1α) and the nuclear receptor PPARβ/δ have both been independently discovered to play a pivotal role in the regulation of oxidative metabolism in skeletal muscle, though their interdependence remains unclear. Hence, our aim was to determine the functional interaction between these two factors in mouse skeletal muscle in vivo. METHODS: Adult male control mice, PGC-1α muscle-specific transgenic (mTg) mice, PPARβ/δ muscle-specific knockout (mKO) mice and the combination PPARβ/δ mKO + PGC-1α mTg mice were studied under basal conditions and following PPARβ/δ agonist administration and acute exercise. Whole-body metabolism was assessed by indirect calorimetry and blood analysis, while magnetic resonance was used to measure body composition. Quantitative PCR and western blot were used to determine gene expression and intracellular signalling. The proportion of oxidative muscle fibre was determined by NADH staining. RESULTS: Agonist-induced PPARβ/δ activation was only disrupted by PPARβ/δ knockout. We also found that the disruption of the PGC-1α-PPARβ/δ axis did not affect whole-body metabolism under basal conditions. As expected, PGC-1α mTg mice exhibited higher exercise performance, peak oxygen consumption and lower blood lactate levels following exercise, though PPARβ/δ mKO + PGC-1α mTg mice showed a similar phenotype. Similarly, we found that PPARβ/δ was dispensable for PGC-1α-mediated enhancement of an oxidative phenotype in skeletal muscle. CONCLUSIONS/INTERPRETATION: Collectively, these results indicate that PPARβ/δ is not an essential partner of PGC-1α in the control of skeletal muscle energy metabolism