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Background Peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α) downregulation in skeletal muscle contributes to insulin resistance and type 2 diabetes mellitus. Here, we examined the effects of endoplasmic reticulum (ER) stress on PGC-1α levels in muscle and the potential mechanisms involved. Methods The human skeletal muscle cell line LHCN-M2 and mice exposed to different inducers of ER stress were used. Results Palmitate- or tunicamycin-induced ER stress resulted in PGC-1α downregulation and enhanced expression of activating transcription factor 4 (ATF4) in human myotubes and mouse skeletal muscle. Overexpression of ATF4 decreased basal PCG-1α expression, whereas ATF4 knockdown abrogated the reduction of PCG-1α caused by tunicamycin in myotubes. ER stress induction also activated mammalian target of rapamycin (mTOR) in myotubes and reduced the nuclear levels of cAMP response element-binding protein (CREB)-regulated transcription co-activator 2 (CRTC2), a positive modulator of PGC-1α transcription. The mTOR inhibitor torin 1 restored PCG-1α and CRTC2 protein levels. Moreover, siRNA against S6 kinase, an mTORC1 downstream target, prevented the reduction in the expression of CRTC2 and PGC-1α caused by the ER stressor tunicamycin. Conclusions Collectively, these findings demonstrate that ATF4 and the mTOR-CRTC2 axis regulates PGC-1α transcription under ER stress conditions in skeletal muscle, suggesting that its inhibition might be a therapeutic target for insulin resistant states. -LYtH6dWBUupjprW9VTowo Video Abstract

Abstract Background: PPP1R6 is a protein phosphatase 1 glycogen-targeting subunit (PP1-GTS) abundant in skeletal muscle with an undefined metabolic control role. Here PPP1R6 effects on myotube glycogen metabolism, particle size and subcellular distribution are examined and compared with PPP1R3C/PTG and PPP1R3A/GM . Results: PPP1R6 overexpression activates glycogen synthase (GS), reduces its phosphorylation at Ser-641/0 and increases the extracted and cytochemically-stained glycogen content, less than PTG but more than GM . PPP1R6 does not change glycogen phosphorylase activity. All tested PP1-GTS-cells have more glycogen particles than controls as found by electron microscopy of myotube sections. Glycogen particle size is distributed for all cell-types in a continuous range, but PPP1R6 forms smaller particles (mean diameter 14.4 nm) than PTG (36.9 nm) and GM (28.3 nm) or those in control cells (29.2 nm). Both PPP1R6- and GM -derived glycogen particles are in cytosol associated with cellular structures; PTG-derived glycogen is found in membrane- and organelle-devoid cytosolic glycogen-rich areas; and glycogen particles are dispersed in the cytosol in control cells. A tagged PPP1R6 protein at the C-terminus with EGFP shows a diffuse cytosol pattern in glucose-replete and -depleted cells and a punctuate pattern surrounding the nucleus in glucose-depleted cells, which colocates with RFP tagged with the Golgi targeting domain of β-1,4-galactosyltransferase, according to a computational prediction for PPP1R6 Golgi location. Conclusions: PPP1R6 exerts a powerful glycogenic effect in cultured muscle cells, more than GM and less than PTG. PPP1R6 protein translocates from a Golgi to cytosolic location in response to glucose. The molecular size and subcellular location of myotube glycogen particles is determined by the PPP1R6, PTG and GM scaffolding.

Research in recent years on peroxisome proliferator-activated receptor (PPAR)β/δ indicates that it plays a key role in the maintenance of energy homeostasis, both at the cellular level and within the organism as a whole. PPARβ/δ activation might help prevent the development of metabolic disorders, including obesity, dyslipidaemia, type 2 diabetes mellitus and non-alcoholic fatty liver disease. This review highlights research findings on the PPARβ/δ regulation of energy metabolism and the development of diseases related to altered cellular and body metabolism. It also describes the potential of the pharmacological activation of PPARβ/δ as a treatment for human metabolic disorders.

The growth arrest and DNA damage inducible 45A (GADD45A) is a multifaceted protein associated with stress signaling and cellular injury. Aside its well-established tumor suppressor activity, recent studies point to additional roles for GADD45A, including the regulation of catabolic and anabolic pathways, or the prevention of inflammation, fibrosis, and oxidative stress in some tissues and organs. However, little is known about its function in cardiac disease. In this study, we aimed to evaluate the role of GADD45A in the heart by using mice with constitutive and systemic deletion of Gadd45a , and cardiac cells of human origin. Gadd45a suppression in knockout mice triggered cardiac fibrosis, inflammation, and apoptosis, and these changes correlated with an hyperactivation of the pro-inflammatory and pro-fibrotic transcription factors activator protein-1 (AP-1), nuclear factor-κB (NF-κB), and signal transducer and activator of transcription 3 (STAT3). Deletion of Gadd45a also resulted in substantial cardiac hypertrophy, which negatively impacted cardiac morphology and function in knockout mice. Consistent with this, GADD45A overexpression in human AC16 cardiomyocytes partially prevented the inflammatory and fibrotic responses induced by tumor necrosis factor-α (TNF-α). Overall, data presented in this study highlight an important role for GADD45A in the heart, since it may prevent inflammation, fibrosis, and apoptosis, and, by this means, preserve cardiac function and performance. Since fibrosis and inflammation are crucial in the progression of cardiac hypertrophy and subsequent heart failure, these results suggest that promoting the activity of this protein might be a promising therapeutic strategy to slow down the progression of these deleterious diseases.

Nuclear growth differentiation factor 15 (GDF15) reduces the binding of the mothers' against decapentaplegic homolog (SMAD) complex to its DNA-binding elements. However, the stimuli that control this process are unknown. Here, we examined whether saturated fatty acids (FA), particularly palmitate, regulate nuclear GDF15 levels and the activation of the SMAD3 pathway in human skeletal myotubes and mouse skeletal muscle, where most insulin-stimulated glucose use occurs in the whole organism. Human LHCN-M2 myotubes and skeletal muscle from wild-type and Gdf15 -/-mice fed a standard (STD) or a high-fat (HFD) diet were subjected to a series of studies to investigate the involvement of lipids in nuclear GDF15 levels and the activation of the SMAD3 pathway. The saturated FA palmitate, but not the monounsaturated FA oleate, increased the expression of GDF15 in human myotubes and, unexpectedly, decreased its nuclear levels. This reduction was prevented by the nuclear export inhibitor leptomycin B. The decrease in nuclear GDF15 levels caused by palmitate was accompanied by increases in SMAD3 protein levels and in the expression of its target gene SERPINE1, which encodes plasminogen activator inhibitor 1 (PAI-1). HFD-fed Gdf15 -/-mice displayed aggravated glucose intolerance compared to HFD-fed WT mice, with increased levels of SMAD3 and PAI-1 in the skeletal muscle. The increased PAI-1 levels in the skeletal muscle of HFD-fed Gdf15 -/-mice were accompanied by a reduction in one of its targets, hepatocyte growth factor (HGF)α, a cytokine involved in glucose metabolism. Interestingly, PAI-1 acts as a ligand of signal transducer and activator of transcription 3 (STAT3) and the phosphorylation of this transcription factor was exacerbated in HFD-fed Gdf15 -/-mice compared to HFD-fed WT mice. At the same time, the protein levels of insulin receptor substrate 1 (IRS-1) were reduced. These findings uncover a potential novel mechanism through which palmitate induces the SMAD3-PAI-1 pathway to promote insulin resistance in skeletal muscle by reducing nuclear GDF15 levels.