bims-exemet 2021-03-28 papers

Issue of 2021–03–28
eight papers selected by
Javier Botella Ruiz, Victoria University

FASEB J. 2021 Apr;35(4): e21453

Chronic exercise training activates histone turnover in mouse skeletal muscle fibers.

Epigenetic regulation of skeletal muscle adaptation to exercise is a recent topic for which there is limited information. This study investigated whether exercise training activates histone turnover in the skeletal muscle fibers of mice. Experiments using a tetracycline-inducible H2B-GFP expression model demonstrated that 4 weeks of running training, but not 2 weeks of training, significantly promoted the incorporation of H2B-GFP into nucleosomes and the dissociation of histone H3.3 at both transcriptionally upregulated and nonresponsive loci. Muscle-specific PGC-1α-b-overexpressing mice crossed with H2B-GFP mice showed a slight increase in H2B-GFP incorporation at transcriptionally active loci, but not in the dissociation of H3.3 from nucleosomes. Gene expression responses to a single bout of running were significantly enhanced in 4-week trained mice when compared with those in 2-week trained mice. The most drastic increase in the gene response was found in the expression of Hspa1a and Hspa1b, in which the magnitude of upregulation in response to running was significantly enhanced from 8-fold in 2 week trained mice to 97- and 121-fold in 4 week trained mice, respectively. It was also found that the HSP70 level increased during the training period. In a myonuclear immunohistochemical analysis of chromatin remodelers, we further found that the level of SPT16, an H2A-H2B-specific chaperone, was upregulated after running training. These results revealed that 4 weeks of running training activated histone turnover in skeletal muscle fibers. They also suggested that histone turnover led to loosening of the nucleosomes and enhanced gene responses to exercise.

Keywords: H2B-GFP; exercise training; histone modification; myonucleus; skeletal muscle

DOI: https://doi.org/10.1096/fj.202002027RR

Cell Metab. 2021 Mar 19. pii: S1550-4131(21)00111-X. [Epub ahead of print]

Placental superoxide dismutase 3 mediates benefits of maternal exercise on offspring health.

Poor maternal diet increases the risk of obesity and type 2 diabetes in offspring, adding to the ever-increasing prevalence of these diseases. In contrast, we find that maternal exercise improves the metabolic health of offspring, and here, we demonstrate that this occurs through a vitamin D receptor-mediated increase in placental superoxide dismutase 3 (SOD3) expression and secretion. SOD3 activates an AMPK/TET signaling axis in fetal offspring liver, resulting in DNA demethylation at the promoters of glucose metabolic genes, enhancing liver function, and improving glucose tolerance. In humans, SOD3 is upregulated in serum and placenta from physically active pregnant women. The discovery of maternal exercise-induced cross talk between placenta-derived SOD3 and offspring liver provides a central mechanism for improved offspring metabolic health. These findings may lead to novel therapeutic approaches to limit the transmission of metabolic disease to the next generation.

Keywords: AMPK; DNA methylation; TET; glucose metabolism; maternal exercise; placenta; pregnancy; superoxide dismutase 3; vitamin D

DOI: https://doi.org/10.1016/j.cmet.2021.03.004

J Physiol. 2021 Mar 24.

Low-volume high-intensity interval training for cardiometabolic health.

Angelo Sabag, Johnathan P Little, Nathan A Johnson.

KEY POINTS: Low-volume HIIT is an efficacious and time efficient therapy for improving the cardiometabolic health of individuals with or at risk of metabolic disease, including in the absence of significant weight loss. Findings from the available literature indicate that low-volume HIIT elicits comparable, and at times superior, improvements in cardiometabolic health outcomes to higher volume moderate-intensity exercise despite requiring less time and energy expenditure. Low-volume HIIT appears to be safe and well tolerated, including in people with compromised metabolic and cardiovascular health.
ABSTRACT: High-intensity interval training (HIIT) is characterised by short bouts of high-intensity submaximal exercise interspersed with rest periods. Low-volume HIIT, typically involving less than 15 minutes of high-intensity exercise per session, is being increasingly investigated in healthy and clinical populations due to its time-efficient nature and purported health benefits. The findings from recent trials suggest that low-volume HIIT can induce similar, and at times greater, improvements in cardiorespiratory fitness, glucose control, blood pressure, and cardiac function when compared to more traditional forms of aerobic exercise training including high-volume HIIT and moderate intensity continuous training, despite requiring less time commitment and lower energy expenditure. Although further studies are required to elucidate the precise mechanisms of action, metabolic improvements appear to be driven, in part, by enhanced mitochondrial function and insulin sensitivity, whereas certain cardiovascular improvements are linked to increased left ventricular function as well as greater central and peripheral arterial compliance. Beyond the purported health benefits, low-volume HIIT appears to be safe and well-tolerated in adults, with high rates of reported exercise adherence and low adverse effects. This article is protected by copyright. All rights reserved.

Keywords: HIIT; aerobic exercise; obesity

DOI: https://doi.org/10.1113/JP281210

FEBS J. 2021 Mar 23.

Cellular and Molecular Pathways Controlling Muscle Size in Response to Exercise.

Michael Attwaters, Simon M Hughes.

From the discovery of ATP and motor proteins to synaptic neurotransmitters and growth factor control of cell differentiation, skeletal muscle has provided an extreme model system in which to understand aspects of tissue function. Muscle is one of the few tissues that can undergo both increase and decrease in size during everyday life. Muscle size depends on its contractile activity, but the precise cellular and molecular pathway(s) by which the activity stimulus influences muscle size and strength remain unclear. Four correlates of muscle contraction could, in theory, regulate muscle growth: nerve-derived signals, cytoplasmic calcium dynamics, the rate of ATP consumption, and physical force. Here, we summarize the evidence for and against each stimulus and what is known or remains unclear concerning their molecular signal transduction pathways and cellular effects. Skeletal muscle can grow in three ways, by generation of new syncytial fibres, addition of nuclei from muscle stem cells to existing fibres or increase in cytoplasmic volume/nucleus. Evidence suggests the latter two processes contribute to exercise-induced growth. Fibre growth requires increase in sarcolemmal surface area and cytoplasmic volume at different rates. It has long been known that high force exercise is a particularly effective growth stimulus, but how this stimulus is sensed and drives coordinated growth that is appropriately scaled across organelles remains a mystery.

Keywords: calcium; energy; exercise; force; growth; hypertrophy; muscle

DOI: https://doi.org/10.1111/febs.15820

Diabetologia. 2021 Mar 26.

Exercise training improves mitochondrial respiration and is associated with an altered intramuscular phospholipid signature in women with obesity.

Amy E Mendham, Julia H Goedecke, Yingxu Zeng, Steen Larsen, Cindy George, Jon Hauksson, Melony C Fortuin-de Smidt, Alexander V Chibalin, Tommy Olsson, Elin Chorell.

AIMS/HYPOTHESIS: We sought to determine putative relationships among improved mitochondrial respiration, insulin sensitivity and altered skeletal muscle lipids and metabolite signature in response to combined aerobic and resistance training in women with obesity.
METHODS: This study reports a secondary analysis of a randomised controlled trial including additional measures of mitochondrial respiration, skeletal muscle lipidomics, metabolomics and protein content. Women with obesity were randomised into 12 weeks of combined aerobic and resistance exercise training (n = 20) or control (n = 15) groups. Pre- and post-intervention testing included peak oxygen consumption, whole-body insulin sensitivity (intravenous glucose tolerance test), skeletal muscle mitochondrial respiration (high-resolution respirometry), lipidomics and metabolomics (mass spectrometry) and lipid content (magnetic resonance imaging and spectroscopy). Proteins involved in glucose transport (i.e. GLUT4) and lipid turnover (i.e. sphingomyelin synthase 1 and 2) were assessed by western blotting.
RESULTS: The original randomised controlled trial showed that exercise training increased insulin sensitivity (median [IQR]; 3.4 [2.0-4.6] to 3.6 [2.4-6.2] x10-5 pmol l-1 min-1), peak oxygen consumption (mean ± SD; 24.9 ± 2.4 to 27.6 ± 3.4 ml kg-1 min-1), and decreased body weight (84.1 ± 8.7 to 83.3 ± 9.7 kg), with an increase in weight (pre intervention, 87.8± 10.9 to post intervention 88.8 ± 11.0 kg) in the control group (interaction p < 0.05). The current study shows an increase in mitochondrial respiration and content in response to exercise training (interaction p < 0.05). The metabolite and lipid signature at baseline were significantly associated with mitochondrial respiratory capacity (p < 0.05) but were not associated with whole-body insulin sensitivity or GLUT4 protein content. Exercise training significantly altered the skeletal muscle lipid profile, increasing specific diacylglycerol(32:2) and ceramide(d18:1/24:0) levels, without changes in other intermediates or total content of diacylglycerol and ceramide. The total content of cardiolipin, phosphatidylcholine (PC) and phosphatidylethanolamine (PE) increased with exercise training with a decrease in the PC:PE ratios containing 22:5 and 20:4 fatty acids. These changes were associated with content-driven increases in mitochondrial respiration (p < 0.05), but not with the increase in whole-body insulin sensitivity or GLUT4 protein content. Exercise training increased sphingomyelin synthase 1 (p < 0.05), with no change in plasma-membrane-located sphingomyelin synthase 2.
CONCLUSIONS/INTERPRETATION: The major findings of our study were that exercise training altered specific intramuscular lipid intermediates, associated with content-driven increases in mitochondrial respiration but not whole-body insulin sensitivity. This highlights the benefits of exercise training and presents putative target pathways for preventing lipotoxicity in skeletal muscle, which is typically associated with the development of type 2 diabetes.

Keywords: Acylcarnitines; Aerobic and resistance training; Cardiolipins; Cardiorespiratory fitness; Ectopic fat; Mitochondrial biogenesis; Obesity; Phospholipid hydrolysis; Sphingomyelin; Triacylglycerol

DOI: https://doi.org/10.1007/s00125-021-05430-6

Physiol Rep. 2021 Mar;9(6): e14797

Ammonium chloride administration prior to exercise has muscle-specific effects on mitochondrial and myofibrillar protein synthesis in rats.

Amanda J Genders, Evelyn C Marin, Joseph J Bass, Jujiao Kuang, Nicholas J Saner, Ken Smith, Philip J Atherton, David J Bishop.

AIM: Exercise is able to increase both muscle protein synthesis and mitochondrial biogenesis. However, acidosis, which can occur in pathological states as well as during high-intensity exercise, can decrease mitochondrial function, whilst its impact on muscle protein synthesis is disputed. Thus, the aim of this study was to determine the effect of a mild physiological decrease in pH, by administration of ammonium chloride, on myofibrillar and mitochondrial protein synthesis, as well as associated molecular signaling events.
METHODS: Male Wistar rats were given either a placebo or ammonium chloride prior to a short interval training session. Rats were killed before exercise, immediately after exercise, or 3 h after exercise.
RESULTS: Myofibrillar (p = 0.036) fractional protein synthesis rates was increased immediately after exercise in the soleus muscle of the placebo group, but this effect was absent in the ammonium chloride group. However, in the gastrocnemius muscle NH4 Cl increased myofibrillar (p = 0.044) and mitochondrial protein synthesis (0 h after exercise p = 0.01; 3 h after exercise p = 0.003). This was accompanied by some small differences in protein phosphorylation and mRNA expression.
CONCLUSION: This study found ammonium chloride administration immediately prior to a single session of exercise in rats had differing effects on mitochondrial and myofibrillar protein synthesis rates in soleus (type I) and gastrocnemius (type II) muscle in rats.

Keywords: acidosis; exercise; mitochondria; protein synthesis; skeletal muscle

DOI: https://doi.org/10.14814/phy2.14797

Eur J Appl Physiol. 2021 Mar 20.

Regulation of satellite cells by exercise in hypoxic conditions: a narrative review.

Sophie van Doorslaer de Ten Ryen, Marc Francaux, Louise Deldicque.

PURPOSE: To investigate in vivo the adaptations of satellite cell induced by exercise performed in acute or chronic hypoxic conditions and their contribution to muscle remodeling and hypertrophy.
METHODS: Search terms related to exercise, hypoxia and satellite cells were entered on Embase, PubMed and Scopus. Studies were selected for their relevance in terms of regulation of satellite cells by in vivo exercise and muscle contraction in hypoxic conditions.
RESULTS: Satellite cell activation and proliferation seem to be enabled after acute hypoxic exercise via regulations induced by myogenic regulatory factors. Several studies reported also a role of the inflammatory pathway nuclear factor-kappa B and angiogenic factors such as vascular endothelial growth factor, both known to upregulate myogenesis. By stimulating angiogenesis, repeated exercise performed in acute hypoxia might contribute to satellite cell activation. Contrary to such exercise conditions, chronic exposure to hypoxia downregulates myogenesis despite the maintenance of physical activity. This impaired myogenesis might be induced by excessive oxidative stress and proteolysis.
CONCLUSION: In vivo studies suggest that, in comparison to exercise or hypoxia alone, exercise performed in a hypoxic environment, may improve or impair muscle remodeling induced by contractile activity depending upon the duration of hypoxia. Satellite cells seem to be major actors in these dichotomous adaptations. Further research on the role of angiogenesis, types of contraction and autophagy is needed for a better understanding of their respective role in hypoxic exercise-induced modulations of satellite cell activity in human.

Keywords: Angiogenesis; Autophagy; Hypertrophy; Hypoxia; Inflammation; Satellite cell; Skeletal muscle

DOI: https://doi.org/10.1007/s00421-021-04641-4

Front Nutr. 2021 ;8 627289

Is There an Exercise-Intensity Threshold Capable of Avoiding the Leaky Gut?

Filipe M Ribeiro, Bernardo Petriz, Gabriel Marques, Lima H Kamilla, Octavio L Franco.

Endurance-sport athletes have a high incidence of gastrointestinal disorders, compromising performance and impacting overall health status. An increase in several proinflammatory cytokines and proteins (LPS, I-FABP, IL-6, IL-1β, TNF-α, IFN-γ, C-reactive protein) has been observed in ultramarathoners and triathlon athletes. One of the most common effects of this type of physical activity is the increase in intestinal permeability, known as leaky gut. The intestinal mucosa's degradation can be identified and analyzed by a series of molecular biomarkers, including the lactulose/rhamnose ratio, occludin and claudin (tight junctions), lipopolysaccharides, and I-FABP. Identifying the molecular mechanisms involved in the induction of leaky gut by physical exercise can assist in the determination of safe exercise thresholds for the preservation of the gastrointestinal tract. It was recently shown that 60 min of vigorous endurance training at 70% of the maximum work capacity led to the characteristic responses of leaky gut. It is believed that other factors may contribute to this effect, such as altitude, environmental temperature, fluid restriction, age and trainability. On the other hand, moderate physical training and dietary interventions such as probiotics and prebiotics can improve intestinal health and gut microbiota composition. This review seeks to discuss the molecular mechanisms involved in the intestinal mucosa's adaptation and response to exercise and discuss the role of the intestinal microbiota in mitigating these effects.

Keywords: exercise threshold; gastrointestinal disorder; gut injury; gut microbiota; leaky gut

DOI: https://doi.org/10.3389/fnut.2021.627289