Excess of Free Fatty Acids as a Cause of Metabolic Dysfunction in Skeletal Muscle

Tůmová, Jana; Andĕl, M; Trnka, Ján

doi:10.33549/physiolres.932993

Cited by 111 publications

(77 citation statements)

References 111 publications

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“…High levels of palmitate have been shown to cause mitochondrial lipotoxicity, ROS production and cell death in skeletal muscle cells (Martins et al 2012;Tumova et al 2016). Interestingly, we showed that PGC-1α overexpression prevents palmitate-induced cell death, whereas UCP3 knockdown attenuated PGC-1α protective effect (Fig.…”

Section: Ucp3 Is Essential For Pgc-1α-induced Mitochondrial Functionmentioning

confidence: 68%

Essential role of the PGC‐1α/PPARβ axis in Ucp3 gene induction

Lima

Guimarães

Sponton

et al. 2019

The Journal of Physiology

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Key points We report that the peroxisome proliferator‐activated receptor (PPAR)γ coactivator 1‐α (PGC‐1α)/PPARβ axis is a crucial mediator of uncoupling protein 3 (UCP3) expression in skeletal muscle cells via the transactivativation of a distal PPAR response element at the Ucp3 gene promoter. This mechanism is activated during the myogenic process and by high concentrations of fatty acids independent of PGC‐1α protein levels. Ucp3 is essential for PGC‐1α‐induced oxidative capacity and the adaptive mitochondrial response to fatty acid exposure. These findings provide further evidence for the broad spectrum of the coactivator action in mitochondrial homeostasis, positioning the PGC‐1ɑ/PPARβ axis as an essential component of the molecular regulation of Ucp3 gene in skeletal muscle cells. Abstract Uncoupling protein 3 (UCP3) has an essential role in fatty acid metabolism and mitochondrial redox regulation in skeletal muscle. However, the molecular mechanisms involved in the expression of Ucp3 are poorly known. In the present study, we show that the peroxisome proliferator‐activated receptor (PPAR)γ coactivator 1‐α (PGC‐1α)/PPARβ axis is a crucial mediator of Ucp3 expression in skeletal muscle cells. In silico analysis of the UCP3 promoter and quantitative chromatin immunoprecipitation experiments revealed that the induction of the UCP3 transcript is mediated by the transactivation of a distal PPAR response element at the Ucp3 gene promoter by the coactivator PGC‐1α. This mechanism is activated during myogenesis and during metabolic stress induced by fatty acids independent of PGC‐1α protein levels. We also provide evidence that Ucp3 is essential for PGC‐1α‐induced oxidative capacity. Taken together, our results highlight PGC‐1ɑ/PPARβ as an essential component of the molecular regulation of Ucp3 gene in skeletal muscle cells.

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Section: Ucp3 Is Essential For Pgc-1α-induced Mitochondrial Functionmentioning

confidence: 68%

Essential role of the PGC‐1α/PPARβ axis in Ucp3 gene induction

Lima

Guimarães

Sponton

et al. 2019

The Journal of Physiology

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“…Although some studies demonstrate that lipotoxicity‐induced apoptosis is a specific effect of saturated FFA, unsaturated FFA is also toxic in an alternative pathway, which suggests that both saturated and unsaturated FFA markedly differ in their contributions to lipotoxicity . Therefore, the combination of both types of FFAs may best reflect the physiological or pathological situation under glucolipotoxicity …”

Section: Introductionmentioning

confidence: 99%

Liraglutide protects against glucolipotoxicity‐induced RIN‐m5F β‐cell apoptosis through restoration of PDX1 expression

Kornelius

Peng

et al. 2018

J Cellular Molecular Medi

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Prolonged exposure to high levels of glucose and fatty acid (FFA) can induce tissue damage commonly referred to as glucolipotoxicity and is particularly harmful to pancreatic β‐cells. Glucolipotoxicity‐mediated β‐cell failure is a critical causal factor in the late stages of diabetes, which suggests that mechanisms that prevent or reverse β‐cell death may play a critical role in the treatment of the disease. Transcription factor PDX1 was recently reported to play a key role in maintaining β‐cell function and survival, and glucolipotoxicity can activate mammalian sterile 20‐like kinase 1 (Mst1), which, in turn, stimulates PDX1 degradation and causes dysfunction and apoptosis of β‐cells. Interestingly, previous research has demonstrated that increased glucagon‐like peptide‐1 (GLP‐1) signalling effectively protects β cells from glucolipotoxicity‐induced apoptosis. Unfortunately, few studies have examined the related mechanism in detail, especially the role in Mst1 and PDX1 regulation. In the present study, we investigate the toxic effect of high glucose and FFA levels on rat pancreatic RINm5F β‐cells and demonstrate that the GLP‐1 analogue liraglutide restores the expression of PDX1 by inactivating Mst1, thus ameliorating β‐cell impairments. In addition, liraglutide also upregulates mitophagy, which may help restore mitochondrial function and protect β‐cells from oxidative stress damage. Our study suggests that liraglutide may serve as a potential agent for developing new therapies to reduce glucolipotoxicity.

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“…A more general hypothesis of obesity effects is the lipid overflow hypothesis (Mittendorfer, 2011), which suggests that when the individual limits of physical expandability of the adipose tissue are surpassed, other tissues, e.g. skeletal or cardiac muscle, are exposed to excess free fatty acid (FFA) levels, leading to intramyocellular fat storage and mitochondrial stress due to incomplete fatty acid oxidation (Consitt et al 2009;Tumova et al 2016;Schrauwen-Hinderling et al 2016;Di Meo et al 2017). In skeletal muscle it still remains unsettled whether the observed lower ATP synthesis capacity in individuals with obesity (Bakkman et al 2010;Vijgen et al 2013) is due to a lower concentration of mitochondria, dysfunction or a combination of the two (Consitt et al 2009;Holloway et al 2009;Tumova et al 2016;Jorgensen et al 2017).…”

Section: Introductionmentioning

confidence: 99%

“…skeletal or cardiac muscle, are exposed to excess free fatty acid (FFA) levels, leading to intramyocellular fat storage and mitochondrial stress due to incomplete fatty acid oxidation (Consitt et al 2009;Tumova et al 2016;Schrauwen-Hinderling et al 2016;Di Meo et al 2017). In skeletal muscle it still remains unsettled whether the observed lower ATP synthesis capacity in individuals with obesity (Bakkman et al 2010;Vijgen et al 2013) is due to a lower concentration of mitochondria, dysfunction or a combination of the two (Consitt et al 2009;Holloway et al 2009;Tumova et al 2016;Jorgensen et al 2017). Adverse effects of obesity in skeletal muscle on the mitochondrial electron transport chain (Ritov et al 2010) and on expression of genes of the oxidative metabolism and mitochondrial biogenesis, such as the peroxisome proliferator-activated receptor γ (PPAR-γ) and PPAR co-activator 1 α (PGC-1α) (Maples et al 2015), have been reported.…”

Section: Introductionmentioning

confidence: 99%

Unchanged mitochondrial phenotype, but accumulation of lipids in the myometrium in obese pregnant women

Gam

Larsen

Mortensen

et al. 2017

The Journal of Physiology

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Obesity is known to increase the risk of labour dystocia and insufficient energy supply, due to reduced mitochondrial capacity or quantity, could be a possible mechanism leading to reduced efficiency of uterine contractility during labour. In the present study of 36 women having an elective Caesarean section at term, obesity did not change mitochondrial phenotype in the myometrial myocyte obtained from uterine biopsies taken at delivery. Respiration rates in isolated mitochondria were unaffected by obesity. No indication of reduced content, investigated by quantification of the complexes of the respiratory chain, or altered regulation, examined by myometrial mRNA levels of genes related to mitochondrial biogenesis and inflammation, was detected. Yet we found increased myometrial triglyceride content in the obese group (2.39 ± 0.26 vs. 1.56 ± 0.20 mm, P = 0.024), while protein content and citrate synthase activity per gram wet weight myometrium were significantly lower in the obese (109.2 ± 7.2 vs. 139.4 ± 5.6 mg g , P = 0.002, and 24.8 ± 1.0 vs. 29.6 ± 1.4 U g wet wt, P = 0.008, respectively). These differences were substantiated by our histological findings where staining for nuclei, cytoplasm, glycogen and collagen supported the idea of a smaller muscle content in the myometrium in obese women. In conclusion no indication of myometrial mitochondrial dysfunction in the isolated state was found, but the observed increase of lipid content might play a role in the pathophysiological mechanisms behind labour dystocia in obese women.

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Excess of Free Fatty Acids as a Cause of Metabolic Dysfunction in Skeletal Muscle

Cited by 111 publications

References 111 publications

Essential role of the PGC‐1α/PPARβ axis in Ucp3 gene induction

Essential role of the PGC‐1α/PPARβ axis in Ucp3 gene induction

Liraglutide protects against glucolipotoxicity‐induced RIN‐m5F β‐cell apoptosis through restoration of PDX1 expression

Unchanged mitochondrial phenotype, but accumulation of lipids in the myometrium in obese pregnant women

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