The Regulatory Roles of PPARs in Skeletal Muscle Fuel Metabolism and Inflammation: Impact of PPAR Agonism on Muscle in Chronic Disease, Contraction and Sepsis

The peroxisome proliferator-activated receptor (PPAR) family of transcription factors has been demonstrated to play critical roles in regulating fuel selection, energy expenditure and inflammation in skeletal muscle and other tissues. Activation of PPARs, through endogenous fatty acids and fatty acid metabolites or synthetic compounds, has been demonstrated to have lipid-lowering and anti-diabetic actions. This review will aim to provide a comprehensive overview of the functions of PPARs in energy homeostasis, with a focus on the impacts of PPAR agonism on muscle metabolism and function. The dysregulation of energy homeostasis in skeletal muscle is a frequent underlying characteristic of inflammation-related conditions such as sepsis. However, the potential benefits of PPAR agonism on skeletal muscle protein and fuel metabolism under these conditions remains under-investigated and is an area of research opportunity. Thus, the effects of PPARγ agonism on muscle inflammation and protein and carbohydrate metabolism will be highlighted, particularly with its potential relevance in sepsis-related metabolic dysfunction. The impact of PPARδ agonism on muscle mitochondrial function, substrate metabolism and contractile function will also be described

The impact of immobilisation and inflammation on the regulation of muscle mass and insulin resistance: different routes to similar end points

Loss of muscle mass and insulin sensitivity are common phenotypic traits of immobilisation and increased inflammatory burden. The suppression of muscle protein synthesis is the primary driver of muscle mass loss in human immobilisation, and includes blunting of post‐prandial increases in muscle protein synthesis. However, the mechanistic drivers of this suppression are unresolved. Immobilisation also induces limb insulin resistance in humans, which appears to be attributable to the reduction in muscle contraction per se. Again mechanistic insight is missing however, such that we do not know how muscle senses its “inactivity status” or whether the proposed drivers of muscle insulin resistance are simply arising as a consequence of immobilisation. An heightened inflammatory state is associated with major and rapid changes in muscle protein turnover and mass, and dampened insulin‐stimulated glucose disposal and oxidation in both rodents and humans. A limited amount of research has attempted to elucidate molecular regulators of muscle mass loss and insulin resistance during increased inflammatory burden, but rarely concurrently. Nevertheless, there is evidence that Akt (protein kinase B) signalling and FOXO transcription factors form part of a common signalling pathway in this scenario, such that molecular cross‐talk between atrophy and insulin signalling during heightened inflammation is believed to be possible (Fig. 1). To conclude, whilst muscle mass loss and insulin resistance are common end‐points of immobilisation and increased inflammatory burden, a lack of understanding of the mechanisms responsible for these traits exists such that a substantial gap in understanding of the pathophysiology in humans endures

Mitochondrial DNA copy number associates with insulin sensitivity and aerobic capacity, and differs between sedentary, overweight middle-aged males with and without type 2 diabetes

Background/objectives: Increased risk of type 2 diabetes mellitus (T2DM) is linked to impaired muscle mitochondrial function and reduced mitochondrial DNA copy number (mtDNAnum). However, studies have failed to control for habitual physical activity levels, which directly influences both mtDNA copy number and insulin sensitivity. We, therefore, examined whether physical conditioning status (maximal oxygen uptake, V̇O2max) was associated with skeletal muscle mitochondrial volume and mtDNAnum, and was predictive of T2DM in overweight, middle-aged men.Methods: Whole-body physiological (ISI-insulin sensitivity index, HOMA-IR, V̇O2max) and muscle biochemical/molecular (vastus lateralis; mtDNAnum, mitochondrial and glycolytic enzymes activity, lipid content and markers of lipid peroxidation) measurements were performed in 3 groups of overweight, middle-aged male volunteers (n=10 per group): sedentary T2DM (ST2DM); sedentary control (SC) and non-sedentary control (NSC), who differed in aerobic capacity (ST2D

Do Antiretroviral Drugs Protect From Multiple Sclerosis By Inhibiting Expression Of MS-Associated Retrovirus?

The expression of human endogenous retroviruses (HERVs) has been associated with Multiple Sclerosis (MS). The MS-related retrovirus (MSRV/HERV-W) has the potential to activate inflammatory immunity, which could promote both susceptibility and progression towards MS. A connection between HERVs and MS is also supported by the observation that people infected with the human immunodeficiency virus (HIV) may have a lower risk of developing MS than the HIV non-infected, healthy population. This may be due to suppression of HERV expression by antiretroviral therapies (ART) used to treat HIV infection.In this pilot study, we compared RNA expression of the envelope gene of MSRV/HERV-W, as well as Toll-like receptors (TLR) 2 and 4, in a small cohort of HIV+ patients with MS patients and healthy controls (HC). An increased expression of MSRV/HERV-Wenv and TLR2 RNA was detected in blood of MS patients compared with HIV patients and HC, while TLR4 was increased in both MS and HIV patients. There was, however, no difference in MSRV/HERV-Wenv, TLR2 and TLR4 expression between ART-treated and -untreated HIV patients. The viral protein Env was expressed mainly by B cells and monocytes, but not by T cells and EBV infection could induce the expression of MSRV/HERV-Wenv in Lymphoblastoid cell lines (LCLs). LCLs were therefore used as an in vitro system to test the efficacy of ART in inhibiting the expression of MSRV/HERV-Wenv. Efavirenz (a non-nucleoside reverse transcriptase inhibitor) alone or different combined drugs could reduce MSRV/HERV-Wenv expression in vitro. Further experiments are needed to clarify the potential role of ART in protection from MS

Major elective abdominal surgery acutely impairs lower limb muscle pyruvate dehydrogenase complex activity and mitochondrial function

© 2020 The Author(s) Background & aims: This post hoc study aimed to determine whether major elective abdominal surgery had any acute impact on mitochondrial pyruvate dehydrogenase complex (PDC) activity and maximal mitochondrial ATP production rates (MAPR) in a large muscle group (vastus lateralis -VL) distant to the site of surgical trauma. Methods: Fifteen patients undergoing major elective open abdominal surgery were studied. Muscle biopsies were obtained after the induction of anesthesia from the VL immediately before and after surgery for the determination of PDC and maximal MAPR (utilizing a variety of energy substrates). Results: Muscle PDC activity was reduced by >50% at the end of surgery compared with pre-surgery (p < 0.05). Muscle MAPR were comprehensively suppressed by surgery for the substrate combinations: glutamate + succinate; glutamate + malate; palmitoylcarnitine + malate; and pyruvate + malate (all p < 0.05), and could not be explained by a lower mitochondrial yield. Conclusions: PDC activity and mitochondrial ATP production capacity were acutely impaired in muscle distant to the site of surgical trauma. In keeping with the limited data available, we surmise these events resulted from the general anesthesia procedures employed and the surgery related trauma. These findings further the understanding of the acute dysregulation of mitochondrial function in muscle distant to the site of major surgical trauma in patients, and point to the combination of general anesthesia and trauma related inflammation as being drivers of muscle metabolic insult that warrants further investigation. Clinical trial registration: Registered at (NCT01134809)

Effects of Endotoxaemia on Protein Metabolism in Rat Fast-Twitch Skeletal Muscle and Myocardium

It is unclear if the rat myocardium undergoes the same rapid reductions in protein content that are classically observed in fast-twitch skeletal muscle during endotoxaemia.To investigate this further, and to determine if there is any divergence in the response of skeletal muscle and myocardium in the mechanisms that are thought to be largely responsible for eliciting changes in protein content, Sprague Dawley rats were implanted with vascular catheters and administered lipopolysaccharide (LPS; 150 microg kg(-1) h(-1)) intravenously for 2 h, 6 h or 24 h (saline administered control animals were also included), after which the extensor digitorum longus (EDL) and myocardium were removed under terminal anaesthesia. The protein-to-DNA ratio, a marker of protein content, was significantly reduced in the EDL following 24 h LPS administration (23%; P<0.05), but was no different from controls in the myocardium. At the same time point, a significant increase in MAFbx/atrogin-1 and MuRF1 mRNA (3.7+/-0.7- and 19.5+/-1.9-fold increase vs. controls, respectively; P<0.05), in addition to protein levels of alpha1-3, 5-7 subunits of the 20S proteasome, were observed in EDL but not myocardium. In contrast, elevations in phosphorylation of p70 S6K residues Thr(421)/Ser(424), and 4E-BP1 residues Thr(37)/Thr(46) (P<0.05), consistent with an elevation in translation initiation, were seen exclusively in the myocardium of LPS-treated animals.In summary, these findings suggest that the myocardium does not undergo the same catabolic response as skeletal muscle during early endotoxaemia, partly due to the absence of transcriptional and signalling events in the myocardium typically associated with increased muscle proteolysis and the suppression of protein synthesis

Potential role for pyruvate kinase M2 in the regulation of murine cardiac glycolytic flux during in vivo chronic hypoxia

Carbohydrate metabolism in heart failure shares similarities to that following hypoxic exposure, and is thought to maintain energy homeostasis in the face of reduced O2 availability. As part of these in vivo adaptations during sustained hypoxia, the heart upregulates and maintains a high glycolytic flux, but the underlying mechanism it is still elusive. We followed the cardiac glycolytic responses to a chronic hypoxic (CH) intervention using [5-3H]-glucose labelling in combination with detailed and extensive enzymatic and metabolomic approaches to provide evidence of the underlying mechanism that allows heart survivability. Following three weeks of in vivo hypoxia (11% oxygen), murine hearts were isolated and perfused in a retrograde mode with function measured via an intraventricular balloon and glycolytic flux quantified using [5-3H]-glucose labelling. At the end of perfusion, hearts were flash-frozen and central carbon intermediates determined via liquid chromatography tandem mass spectrometry (LC-MS/MS). The maximal activity of glycolytic enzymes considered rate-limiting was assessed enzymatically, and protein abundance was determined using Western blotting. Relative to normoxic hearts, CH increased ex vivo cardiac glycolytic flux 1.7-fold with no effect on cardiac function. CH upregulated cardiac pyruvate kinase (PK) flux 3.1-fold and cardiac pyruvate kinase M2 (PKM2) protein content 1.4-fold compared to normoxic hearts. CH also augmented cardiac pentose phosphate pathway flux, reflected by higher ribose-5-phosphate content. These findings support an increase in the covalent (protein expression) and allosteric (flux) control of PKM2 as being central to the sustained upregulation of the glycolytic flux in the chronically hypoxic heart

Whole-body & muscle responses to aerobic exercise training and withdrawal in ageing & COPD

BACKGROUND: Chronic obstructive pulmonary disease (COPD) patients exhibit lower peak oxygen uptake (V′(O(2))(peak)), altered muscle metabolism and impaired exercise tolerance compared with age-matched controls. Whether these traits reflect muscle-level deconditioning (impacted by ventilatory constraints) and/or dysfunction in mitochondrial ATP production capacity is debated. By studying aerobic exercise training (AET) at a matched relative intensity and subsequent exercise withdrawal period we aimed to elucidate the whole-body and muscle mitochondrial responsiveness of healthy young (HY), healthy older (HO) and COPD volunteers to whole-body exercise. METHODS: HY (n=10), HO (n=10) and COPD (n=20) volunteers were studied before and after 8 weeks of AET (65% V′(O(2))(peak)) and after 4 weeks of exercise withdrawal. V′(O(2))(peak), muscle maximal mitochondrial ATP production rate (MAPR), mitochondrial content, mitochondrial DNA (mtDNA) copy number and abundance of 59 targeted fuel metabolism mRNAs were determined at all time-points. RESULTS: Muscle MAPR (normalised for mitochondrial content) was not different for any substrate combination in HO, HY and COPD at baseline, but mtDNA copy number relative to a nuclear-encoded housekeeping gene (mean±sd) was greater in HY (804±67) than in HO (631±69; p=0.041). AET increased V′(O(2))(peak) in HO (17%; p=0.002) and HY (21%; p<0.001), but not COPD (p=0.603). Muscle MAPR for palmitate increased with training in HO (57%; p=0.041) and HY (56%; p=0.003), and decreased with exercise withdrawal in HO (−45%; p=0.036) and HY (−30%; p=0.016), but was unchanged in COPD (p=0.594). mtDNA copy number increased with AET in HY (66%; p=0.001), but not HO (p=0.081) or COPD (p=0.132). The observed changes in muscle mRNA abundance were similar in all groups after AET and exercise withdrawal. CONCLUSIONS: Intrinsic mitochondrial function was not impaired by ageing or COPD in the untrained state. Whole-body and muscle mitochondrial responses to AET were robust in HY, evident in HO, but deficient in COPD. All groups showed robust muscle mRNA responses. Higher relative exercise intensities during whole-body training may be needed to maximise whole-body and muscle mitochondrial adaptation in COPD

Do Antiretroviral Drugs Protect From Multiple Sclerosis by Inhibiting Expression of MS-Associated Retrovirus?

The expression of human endogenous retroviruses (HERVs) has been associated with Multiple Sclerosis (MS). The MS-related retrovirus (MSRV/HERV-W) has the potential to activate inflammatory immunity, which could promote both susceptibility and progression toward MS. A connection between HERVs and MS is also supported by the observation that people infected with the human immunodeficiency virus (HIV) may have a lower risk of developing MS than the HIV non-infected, healthy population. This may be due to suppression of HERV expression by antiretroviral therapies (ART) used to treat HIV infection. In this pilot study, we compared RNA expression of the envelope gene of MSRV/HERV-W, as well as Toll-like receptors (TLR) 2 and 4, in a small cohort of HIV+ patients with MS patients and healthy controls (HC). An increased expression of MSRV/HERV-Wenv and TLR2 RNA was detected in blood of MS patients compared with HIV patients and HC, while TLR4 was increased in both MS and HIV patients. There was, however, no difference in MSRV/HERV-Wenv, TLR2 and TLR4 expression between ART-treated and -untreated HIV patients. The viral protein Env was expressed mainly by B cells and monocytes, but not by T cells and EBV infection could induce the expression of MSRV/HERV-Wenv in Lymphoblastoid cell lines (LCLs). LCLs were therefore used as an in vitro system to test the efficacy of ART in inhibiting the expression of MSRV/HERV-Wenv. Efavirenz (a non-nucleoside reverse transcriptase inhibitor) alone or different combined drugs could reduce MSRV/HERV-Wenv expression in vitro. Further, experiments are needed to clarify the potential role of ART in protection from MS

Inorganic nitrate and nitrite supplementation fails to improve skeletal muscle mitochondrial efficiency in mice and humans

Supported by Medical Research Council program grant MRC G1001340 (to M Madhani, M Feelisch, and MP Frenneaux). We thank Lesley Cheyne for their contributions to the present study. The authors’ responsibilities were as follows—VSV, M Madhani, JDH, MF, DD, MPF: designed the research; MN, NEKP, KS, BLL, M Minnion, BOF, DV, DC-T, PGC: conducted the research; DV: provided essential materials; MN, NEKP, M Minnion, BOF, DC-T, MF, PGC: analyzed the data; MN, NEKP, PGC, MPF: wrote the paper; MPF: had primary responsibility for the final manuscript; and all authors: read and approved the final manuscript. None of the authors reported a conflict of interest related to the study.Peer reviewedPublisher PD