bims-exemet 2021-06-20 papers

Issue of 2021–06–20
seven papers selected by
Javier Botella Ruiz, Victoria University

Nat Metab. 2021 Jun 14.

Pre-operative exercise therapy triggers anti-inflammatory trained immunity of Kupffer cells through metabolic reprogramming.

Hongji Zhang, Tianmeng Chen, Jinghua Ren, Yujia Xia, Amblessed Onuma, Yu Wang, Jiayi He, Junru Wu, Han Wang, Ahmad Hamad, Chengli Shen, Jinxiang Zhang, John M Asara, Gregory K Behbehani, Haitao Wen, Meihong Deng, Allan Tsung, Hai Huang.

Pre-operative exercise therapy improves outcomes for many patients who undergo surgery. Despite the well-known effects on tolerance to systemic perturbation, the mechanisms by which pre-operative exercise protects the organ that is operated on from inflammatory injury are unclear. Here, we show that four-week aerobic pre-operative exercise significantly attenuates liver injury and inflammation from ischaemia and reperfusion in mice. Remarkably, these beneficial effects last for seven more days after completing pre-operative exercising. We find that exercise specifically drives Kupffer cells toward an anti-inflammatory phenotype with trained immunity via metabolic reprogramming. Mechanistically, exercise-induced HMGB1 release enhances itaconate metabolism in the tricarboxylic acid cycle that impacts Kupffer cells in an NRF2-dependent manner. Therefore, these metabolites and cellular/molecular targets can be investigated as potential exercise-mimicking pharmaceutical candidates to protect against liver injury during surgery.

DOI: https://doi.org/10.1038/s42255-021-00402-x

Pflugers Arch. 2021 Jun 17.

The erythropoietin receptor expressed in skeletal muscle is essential for mitochondrial biogenesis and physiological exercise.

Kirsten T Nijholt, Laura M G Meems, Willem P T Ruifrok, Alexander H Maass, Salva R Yurista, Mario G Pavez-Giani, Belend Mahmoud, Anouk H G Wolters, Dirk J van Veldhuisen, Wiek H van Gilst, Herman H W Silljé, Rudolf A de Boer, B Daan Westenbrink.

Erythropoietin (EPO) is a haematopoietic hormone that regulates erythropoiesis, but the EPO-receptor (EpoR) is also expressed in non-haematopoietic tissues. Stimulation of the EpoR in cardiac and skeletal muscle provides protection from various forms of pathological stress, but its relevance for normal muscle physiology remains unclear. We aimed to determine the contribution of the tissue-specific EpoR to exercise-induced remodelling of cardiac and skeletal muscle. Baseline phenotyping was performed on left ventricle and m. gastrocnemius of mice that only express the EpoR in haematopoietic tissues (EpoR-tKO). Subsequently, mice were caged in the presence or absence of a running wheel for 4 weeks and exercise performance, cardiac function and histological and molecular markers for physiological adaptation were assessed. While gross morphology of both muscles was normal in EpoR-tKO mice, mitochondrial content in skeletal muscle was decreased by 50%, associated with similar reductions in mitochondrial biogenesis, while mitophagy was unaltered. When subjected to exercise, EpoR-tKO mice ran slower and covered less distance than wild-type (WT) mice (5.5 ± 0.6 vs. 8.0 ± 0.4 km/day, p < 0.01). The impaired exercise performance was paralleled by reductions in myocyte growth and angiogenesis in both muscle types. Our findings indicate that the endogenous EPO-EpoR system controls mitochondrial biogenesis in skeletal muscle. The reductions in mitochondrial content were associated with reduced exercise capacity in response to voluntary exercise, supporting a critical role for the extra-haematopoietic EpoR in exercise performance.

Keywords: Cardiac and skeletal muscle; Erythropoietin receptor; Exercise performance; Exercise-induced physiological adaptation; Mitochondrial biogenesis

DOI: https://doi.org/10.1007/s00424-021-02577-4

Am J Physiol Endocrinol Metab. 2021 06 14.

Exercise-induced benefits on glucose handling in a model of diet-induced obesity are reduced by concurrent nicotinamide mononucleotide.

Josephine Yu, David Ross Laybutt, Lynn-Jee Kim, Lake-Ee Quek, Lindsay E Wu, Margaret J Morris, Neil A Youngson.

Almost 40% of adults worldwide are classified as overweight or obese. Exercise is a beneficial intervention in obesity, partly due to increases in mitochondrial activity, and subsequent increases in nicotinamide adenine dinucleotide (NAD+), an important metabolic cofactor. Recent studies have shown that increasing NAD+ levels through pharmacological supplementation with precursors such as nicotinamide mononucleotide (NMN) improved metabolic health in high fat diet (HFD) fed mice. However, the effects of combined exercise and NMN supplementation are unknown. Thus here we examined the combined effects of NMN and treadmill exercise in female mice with established obesity after 10 weeks of diet. Five-week old female C57BL/6J mice were exposed to control diet (n=16) or HFD. Sedentary mice fed HFD were either untreated (HFD; n=16), received NMN in drinking water (400mg/kg; HNMN; n=16), were exposed to treadmill exercise 6 days/week (HEx; n=16) or exercise combined with NMN (HNEx; n=16). Whilst some metabolic benefits of NMN have been described, at this dose, NMN administration impaired several aspects of exercise-induced benefits in obese mice, including glucose tolerance, glucose stimulated insulin secretion from islets and reduced hepatic triglyceride accumulation. HNEx mice also exhibited increased antioxidant and reduced prooxidant gene expression in both islets and muscle, suggesting that altered redox status is associated with the loss of exercise-induced health benefits with NMN co-treatment. Our data show that NMN treatment impedes the beneficial metabolic effects of exercise in a mouse model of diet-induced obesity in association with disturbances in redox metabolism.

Keywords: Exercise; Metabolism; Nicotinamide Mononucleotide; Obesity

DOI: https://doi.org/10.1152/ajpendo.00446.2020

Mol Metab. 2021 Jun 09. pii: S2212-8778(21)00115-0. [Epub ahead of print] 101270

Exercise of high intensity ameliorates hepatic inflammation and the progression of NASH.

Gavin Fredrickson, Fanta Barrow, Katrina Dietsche, Preethy Parthiban, Saad Khan, Sacha Robert, Maya Demirchian, Hailey Rhoades, Haiguang Wang, Oyedele Adeyi, Xavier S Revelo.

OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) covers a wide spectrum of liver pathology ranging from simple fatty liver to non-alcoholic steatohepatitis (NASH). Notably, immune cell-driven inflammation is a key mechanism in the transition from fatty liver to the more serious NASH. Although exercise training is effective at ameliorating obesity-related diseases, the underlying mechanisms of the beneficial effects of exercise remain unclear. Whether there is an optimal modality and intensity of exercise to treat NAFLD is unknown. The objective of this study was to determine whether high-intensity interval training (HIIT) or moderate-intensity continuous training (MIT) is more effective at ameliorating the progression of NASH.
METHODS: Wildtype mice were fed a high-fat high-carbohydrate (HFHC) diet for 6 weeks and left sedentary (SED) or assigned to either an MIT or HIIT regimen using treadmill running for an additional 16 weeks. MIT and HIIT groups were pair-fed to ensure energy intake was similar between the exercise cohorts. To determine changes in whole-body metabolism, we performed insulin and glucose tolerance tests, indirect calorimetry, and magnetic resonance imaging. NASH progression was determined by triglyceride accumulation, expression of inflammatory genes, and histological assessment of fibrosis. Immune cell populations in the liver were characterized by cytometry by time-of-flight mass spectrometry and progenitor populations within the bone marrow were assessed by flow cytometry. Finally, we analyzed the transcriptional profile of the liver by bulk RNA sequencing.
RESULTS: Compared with SED mice, both HIIT and MIT suppressed weight gain, improved whole-body metabolic parameters, and ameliorated the progression of NASH by reducing hepatic triglyceride levels, inflammation, and fibrosis. However, HIIT was superior to MIT at reducing adiposity, improving whole-body glucose tolerance, and ameliorating liver steatosis, inflammation, and fibrosis, without any changes in body weight. Improved NASH progression in HIIT mice was accompanied by a substantial decrease in the frequency of pro-inflammatory infiltrating monocyte-derived macrophages in the liver and reduced myeloid progenitor populations in the bone marrow. Notably, an acute bout of MIT or HIIT exercise had no effect on the intrahepatic and splenic immune cell populations. In addition, bulk mRNA sequencing of whole liver tissue showed a pattern of gene expression confirming that HIIT was more effective than MIT in improving liver inflammation and lipid biosynthesis.
CONCLUSIONS: Our data suggest that exercise lessens hepatic inflammation during NASH by reducing the accumulation of hepatic monocyte-derived inflammatory macrophages and bone marrow precursor cells. Our findings also indicate that HIIT is superior to MIT in ameliorating the disease in a dietary mouse model of NASH.

Keywords: Exercise; HIIT; Inflammation; NAFLD; NASH

DOI: https://doi.org/10.1016/j.molmet.2021.101270

Med Sci Sports Exerc. 2021 Jul 01. 53(7): 1375-1384

Substrate-Specific Respiration of Isolated Skeletal Muscle Mitochondria after 1 h of Moderate Cycling in Sedentary Adults.

Sean A Newsom, Harrison D Stierwalt, Sarah E Ehrlicher, Matthew M Robinson.

INTRODUCTION: Skeletal muscle mitochondria have dynamic shifts in oxidative metabolism to meet energy demands of aerobic exercise. Specific complexes oxidize lipid and nonlipid substrates. It is unclear if aerobic exercise stimulates intrinsic oxidative metabolism of mitochondria or varies between substrates.
METHODS: We studied mitochondrial metabolism in sedentary male and female adults (n = 11F/4M) who were free of major medical conditions with mean ± SD age of 28 ± 7 yr, peak aerobic capacity of 2.0 ± 0.4 L·min-1, and body mass index of 22.2 ± 2 kg·m-2. Biopsies were collected from the vastus lateralis muscle on separate study days at rest or 15 min after exercise (1 h cycling at 65% peak aerobic capacity). Isolated mitochondria were analyzed using high-resolution respirometry of separate titration protocols for lipid (palmitoylcarnitine, F-linked) and nonlipid substrates (glutamate-malate, N-linked; succinate S-linked). Titration protocols distinguished between oxidative phosphorylation and leak respiration and included the measurement of reactive oxygen species emission (H2O2). Western blotting determined the protein abundance of electron transfer flavoprotein (ETF) subunits, including inhibitory methylation site on ETF-β.
RESULTS: Aerobic exercise induced modest increases in mitochondrial respiration because of increased coupled respiration across F-linked (+13%, P = 0.08), N(S)-linked (+14%, P = 0.09), and N-linked substrates (+17%, P = 0.08). Prior exercise did not change P:O ratio. Electron leak to H2O2 increased 6% increased after exercise (P = 0.06) for lipid substrates but not for nonlipid. The protein abundance of ETF-α or ETF-β subunit or inhibitory methylation on ETF-β was not different between rest and after exercise.
CONCLUSION: In sedentary adults, the single bout of moderate-intensity cycling induced modest increases for intrinsic mitochondrial oxidative phosphorylation that was consistent across multiple substrates.

DOI: https://doi.org/10.1249/MSS.0000000000002615

J Appl Physiol (1985). 2021 06 17.

Short-term high-fat diet induces muscle fiber type-selective anabolic resistance to resistance exercise.

Satoru Ato, Takahiro Mori, Yuki Fujita, Taiga Mishima, Riki Ogasawara.

Chronic obesity and insulin resistance are considered to inhibit contraction-induced muscle hypertrophy, through impairment of mTORC1 and muscle protein synthesis (MPS). A high-fat diet is known to rapidly induce obesity and insulin resistance within a month. However, the influence of a short-term high-fat diet on the response of mTORC1 activation and MPS to acute resistance exercise (RE) is unclear. Thus, the purpose of this study was to investigate the effect of a short-term high-fat diet on the response of mTORC1 activation and MPS to acute RE. Male Sprague-Dawley rats were randomly assigned to groups and fed a normal diet (ND), high-fat diet (HFD 4wk), or pair feed (PF 4wk) for 4 weeks. After dietary habituation, acute RE was performed on the gastrocnemius muscle via percutaneous electrical stimulation. The results showed that 4 weeks of a high fat-diet induced intramuscular lipid accumulation and insulin resistance, without affecting basal mTORC1 activity or MPS. The response of RE-induced mTORC1 activation and MPS was not altered by a high-fat diet. On the other hand, analysis of each fiber type demonstrated that response of MPS to an acute RE was disappeared specifically in type I and IIa fiber. These results indicate that a short-term high-fat diet causes anabolic resistance to acute RE, depending on the fiber type.

Keywords: high-fat diet; muscle protein synthesis; resistance exercise; ｍTOR

DOI: https://doi.org/10.1152/japplphysiol.00889.2020