bims-exemet 2021-06-13 papers

bims-exemet

Biomed News

on Exercise metabolism

Issue of 2021–06–13
nine papers selected by
Javier Botella Ruiz, Victoria University

Short term intensified training temporarily impairs mitochondrial respiratory capacity in elite endurance athletes.
Time trajectories in the transcriptomic response to exercise - a meta-analysis.
Skeletal Muscle Mitochondrial Function following a 100-km Ultramarathon: A Case Study in Monozygotic Twins.
High intensity muscle stimulation activates a systemic Nrf2-mediated redox stress response.
Satellite Cell Depletion Disrupts Transcriptional Coordination and Muscle Adaptation to Exercise.
Cancer-induced muscle atrophy is determined by intrinsic muscle oxidative capacity.
Exercise mimetics: harnessing the therapeutic effects of physical activity.
Exercise reduces circulating biomarkers of cellular senescence in humans.
Exercise Factors Released by the Liver, Muscle, and Bones Have Promising Therapeutic Potential for Stroke.

J Appl Physiol (1985). 2021 Jun 10.

Short term intensified training temporarily impairs mitochondrial respiratory capacity in elite endurance athletes.

Daniele A Cardinale, Kasper D Gejl, Kristine Grøsfjeld Petersen, Joachim Nielsen, Niels Ørtenblad, Filip J Larsen.

   AIM: The maintenance of healthy and functional mitochondria is the result of a complex mitochondrial turnover and herein quality-control program which includes both mitochondrial biogenesis and autophagy of mitochondria. The aim of this study was to examine the effect of an intensified training load on skeletal muscle mitochondrial quality control in relation to changes in mitochondrial oxidative capacity, maximal oxygen consumption and performance in highly trained endurance athletes.
METHODS: 27 elite endurance athletes performed high intensity interval exercise followed by moderate intensity continuous exercise 3 days per week for 4 weeks in addition to their usual volume of training. Mitochondrial oxidative capacity, abundance of mitochondrial proteins, markers of autophagy and antioxidant capacity of skeletal muscle were assessed in skeletal muscle biopsies before and after the intensified training period.
RESULTS: The intensified training period increased several autophagy markers suggesting an increased turnover of mitochondrial and cytosolic proteins. In permeabilized muscle fibers, mitochondrial respiration was ~20 % lower after training although some markers of mitochondrial density increased by 5-50%, indicative of a reduced mitochondrial quality by the intensified training intervention. The antioxidative proteins UCP3, ANT1, and SOD2 were increased after training, whereas we found an inactivation of aconitase. In agreement with the lower aconitase activity, the amount of mitochondrial LON protease that selectively degrades oxidized aconitase, was doubled.
CONCLUSION: Together, this suggests that mitochondrial respiratory function is impaired during the initial recovery from a period of intensified endurance training while mitochondrial quality control is slightly activated in highly trained skeletal muscle.

Keywords:  athletes; endurance; mitochondrial oxidative capacity; mitochondrial quality-control; mitophagy

DOI:  https://doi.org/10.1152/japplphysiol.00829.2020
Nat Commun. 2021 06 09. 12(1): 3471

Time trajectories in the transcriptomic response to exercise - a meta-analysis.

David Amar, Malene E Lindholm, Jessica Norrbom, Matthew T Wheeler, Manuel A Rivas, Euan A Ashley.

Exercise training prevents multiple diseases, yet the molecular mechanisms that drive exercise adaptation are incompletely understood. To address this, we create a computational framework comprising data from skeletal muscle or blood from 43 studies, including 739 individuals before and after exercise or training. Using linear mixed effects meta-regression, we detect specific time patterns and regulatory modulators of the exercise response. Acute and long-term responses are transcriptionally distinct and we identify SMAD3 as a central regulator of the exercise response. Exercise induces a more pronounced inflammatory response in skeletal muscle of older individuals and our models reveal multiple sex-associated responses. We validate seven of our top genes in a separate human cohort. In this work, we provide a powerful resource ( www.extrameta.org ) that expands the transcriptional landscape of exercise adaptation by extending previously known responses and their regulatory networks, and identifying novel modality-, time-, age-, and sex-associated changes.

DOI: https://doi.org/10.1038/s41467-021-23579-x
Med Sci Sports Exerc. 2021 Jun 07.

Skeletal Muscle Mitochondrial Function following a 100-km Ultramarathon: A Case Study in Monozygotic Twins.

Erik D Marchant, Nathan D Marchant, Robert D Hyldahl, Jayson R Gifford, Michael W Smith, Chad R Hancock.

PURPOSE: Very little research has investigated the effects of ultra-endurance exercise on the bioenergetic status of muscle. The primary objective of this case study was to characterize the changes that occur in skeletal muscle mitochondria in response to a 100-km ultramarathon in monozygotic twins. A second objective was to determine whether mitochondrial function is altered by consuming a periodized low-carbohydrate, high-fat diet (LCHFD) during training compared to a high-carbohydrate diet.
METHODS: One pair of male monozygotic twins ran 100 km on treadmills following 4 weeks of training on either a high carbohydrate or periodized LCHFD. Muscle biopsies were collected 4 weeks prior to the run, as well as 4- and 52-hours post-run. Blood draws were also performed immediately before, as well as 4- and 52-hours post-run.
RESULTS: Four hours post-run, respiratory capacity, citrate synthase activity and mitochondrial complex protein content were decreased. Two days later, both twins showed signs of rapid recovery in several of these measures. Furthermore, blood levels of creatine phosphokinase, C-reactive protein, and aspartate transaminase were elevated 4 hours after the run, but partially recovered two days later.
CONCLUSION: Although there were some differences between the twins, the primary finding is that there is significant mitochondrial impairment induced by running 100 km, which rapidly recovers within 2 days. These results provide ample rationale for future investigations of the effects of ultra-endurance activity on mitochondrial function.

DOI: https://doi.org/10.1249/MSS.0000000000002715
Free Radic Biol Med. 2021 Jun 03. pii: S0891-5849(21)00351-8. [Epub ahead of print]172 82-89

High intensity muscle stimulation activates a systemic Nrf2-mediated redox stress response.

Ethan L Ostrom, Ana P Valencia, David J Marcinek, Tinna Traustadóttir.

  High intensity exercise is a popular mode of exercise to elicit similar or greater adaptive responses compared to traditional moderate intensity continuous exercise. However, the molecular mechanisms underlying these adaptive responses are still unclear. The purpose of this pilot study was to compare high and low intensity contractile stimulus on the Nrf2-mediated redox stress response in mouse skeletal muscle. An intra-animal design was used to control for variations in individual responses to muscle stimulation by comparing a stimulated limb (STIM) to the contralateral unstimulated control limb (CON). High Intensity (HI - 100Hz), Low Intensity (LI - 50Hz), and Naïve Control (NC - Mock stimulation vs CON) groups were used to compare these effects on Nrf2-ARE binding, Keap1 protein, and downstream gene and protein expression of Nrf2 target genes. Muscle stimulation significantly increased Nrf2-ARE binding in LI-STIM compared to LI-CON (p = 0.0098), while Nrf2-ARE binding was elevated in both HI-CON and HI-STIM compared to NC (p = 0.0007). The Nrf2-ARE results were mirrored in the downregulation of Keap1, where Keap1 expression in HI-CON and HI-STIM were both significantly lower than NC (p = 0.008) and decreased in LI-STIM compared to LI-CON (p = 0.015). In addition, stimulation increased NQO1 protein compared to contralateral control regardless of stimulation intensity (p = 0.019), and HO1 protein was significantly higher in high intensity compared to the Naïve control group (p = 0.002). Taken together, these data suggest a systemic redox signaling exerkine is activating Nrf2-ARE binding and is intensity gated, where Nrf2-ARE activation in contralateral control limbs were only seen in the HI group. Other research in exercise induced Nrf2 signaling support the general finding that Nrf2 is activated in peripheral tissues in response to exercise, however the specific exerkine responsible for the systemic signaling effects is not known. Future work should aim to delineate these redox sensitive systemic signaling mechanisms.

Keywords:  High intensity exercise; Muscle contraction; Nrf2-Keap1; Redox signaling

DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.05.039
Function (Oxf). 2021 ;2(1): zqaa033

Satellite Cell Depletion Disrupts Transcriptional Coordination and Muscle Adaptation to Exercise.

Davis A Englund, Vandré C Figueiredo, Cory M Dungan, Kevin A Murach, Bailey D Peck, Jennifer M Petrosino, Camille R Brightwell, Alec M Dupont, Ally C Neal, Christopher S Fry, Federica Accornero, John J McCarthy, Charlotte A Peterson.

  Satellite cells are required for postnatal development, skeletal muscle regeneration across the lifespan, and skeletal muscle hypertrophy prior to maturity. Our group has aimed to address whether satellite cells are required for hypertrophic growth in mature skeletal muscle. Here, we generated a comprehensive characterization and transcriptome-wide profiling of skeletal muscle during adaptation to exercise in the presence or absence of satellite cells in order to identify distinct phenotypes and gene networks influenced by satellite cell content. We administered vehicle or tamoxifen to adult Pax7-DTA mice and subjected them to progressive weighted wheel running (PoWeR). We then performed immunohistochemical analysis and whole-muscle RNA-seq of vehicle (SC+) and tamoxifen-treated (SC-) mice. Further, we performed single myonuclear RNA-seq to provide detailed information on how satellite cell fusion affects myonuclear transcription. We show that while skeletal muscle can mount a robust hypertrophic response to PoWeR in the absence of satellite cells, growth, and adaptation are ultimately blunted. Transcriptional profiling reveals several gene networks key to muscle adaptation are altered in the absence of satellite cells.

Keywords:  Pax7; adaptation; exercise; hypertrophy; muscle function; muscle stem cell; satellite cell

DOI:  https://doi.org/10.1093/function/zqaa033
FASEB J. 2021 Jul;35(7): e21714

Cancer-induced muscle atrophy is determined by intrinsic muscle oxidative capacity.

Christiano R R Alves, Eric J Eichelberger, Willian das Neves, Márcio A C Ribeiro, Luiz R G Bechara, Vanessa A Voltarelli, Ney R de Almeida, Lars Hagen, Animesh Sharma, Julio C B Ferreira, Kathryn J Swoboda, Geir Slupphaug, Patricia C Brum.

  We tested the hypothesis that cancer cachexia progression would induce oxidative post-translational modifications (Ox-PTMs) associated with skeletal muscle wasting, with different responses in muscles with the prevalence of glycolytic and oxidative fibers. We used cysteine-specific isotopic coded affinity tags (OxICAT) and gel-free mass spectrometry analysis to investigate the cysteine Ox-PTMs profile in the proteome of both plantaris (glycolytic) and soleus (oxidative) muscles in tumor-bearing and control rats. Histological analysis revealed muscle atrophy in type II fibers in plantaris muscle, with no changes in plantaris type I fibers and no differences in both soleus type I and II fibers in tumor-bearing rats when compared to healthy controls. Tumor progression altered the Ox-PTMs profile in both plantaris and soleus. However, pathway analysis including the differentially oxidized proteins revealed tricarboxylic acid cycle and oxidative phosphorylation as main affected pathways in plantaris muscle from tumor-bearing rats, while the same analysis did not show main metabolic pathways affected in the soleus muscle. In addition, cancer progression affected several metabolic parameters such as ATP levels and markers of oxidative stress associated with muscle atrophy in plantaris muscle, but not in soleus. However, isolated soleus from tumor-bearing rats had a reduced force production capacity when compared to controls. These novel findings demonstrate that tumor-bearing rats have severe muscle atrophy exclusively in glycolytic fibers. Cancer progression is associated with cysteine Ox-PTMs in the skeletal muscle, but these modifications affect different pathways in a glycolytic muscle compared to an oxidative muscle, indicating that intrinsic muscle oxidative capacity determines the response to cancer cachectic effects.

Keywords:  aerobic metabolism; atrophy; cancer cachexia; fiber type; muscle wasting

DOI:  https://doi.org/10.1096/fj.202100263R
Nat Rev Drug Discov. 2021 Jun 08.

Exercise mimetics: harnessing the therapeutic effects of physical activity.

Carolina Gubert, Anthony J Hannan.

Exercise mimetics are a proposed class of therapeutics that specifically mimic or enhance the therapeutic effects of exercise. Increased physical activity has demonstrated positive effects in preventing and ameliorating a wide range of diseases, including brain disorders such as Alzheimer disease and dementia, cancer, diabetes and cardiovascular disease. This article discusses the molecular mechanisms and signalling pathways associated with the beneficial effects of physical activity, focusing on effects on brain function and cognitive enhancement. Emerging therapeutic targets and strategies for the development of exercise mimetics, particularly in the field of central nervous system disorders, as well as the associated opportunities and challenges, are discussed.

DOI: https://doi.org/10.1038/s41573-021-00217-1
Aging Cell. 2021 Jun 08. e13415

Exercise reduces circulating biomarkers of cellular senescence in humans.

Davis A Englund, Ayumi E Sakamoto, Chad M Fritsche, Amanda A Heeren, Xu Zhang, Brian R Kotajarvi, Denise R Lecy, Matthew J Yousefzadeh, Marissa J Schafer, Thomas A White, Elizabeth J Atkinson, Nathan K LeBrasseur.

  Cellular senescence has emerged as a significant and potentially tractable mechanism of aging and multiple aging-related conditions. Biomarkers of senescent cell burden, including molecular signals in circulating immune cells and the abundance of circulating senescence-related proteins, have been associated with chronological age and clinical parameters of biological age in humans. The extent to which senescence biomarkers are affected by interventions that enhance health and function has not yet been examined. Here, we report that a 12-week structured exercise program drives significant improvements in several performance-based and self-reported measures of physical function in older adults. Impressively, the expression of key markers of the senescence program, including p16, p21, cGAS, and TNFα, were significantly lowered in CD3+ T cells in response to the intervention, as were the circulating concentrations of multiple senescence-related proteins. Moreover, partial least squares discriminant analysis showed levels of senescence-related proteins at baseline were predictive of changes in physical function in response to the exercise intervention. Our study provides first-in-human evidence that biomarkers of senescent cell burden are significantly lowered by a structured exercise program and predictive of the adaptive response to exercise.

Keywords:  aging; immune cells; inflammation; senotherapeutics

DOI:  https://doi.org/10.1111/acel.13415
Front Neurol. 2021 ;12 600365

Exercise Factors Released by the Liver, Muscle, and Bones Have Promising Therapeutic Potential for Stroke.

Joseph S Stephan, Sama F Sleiman.

  Stroke is one of the leading causes of death and disability in the world. Stroke not only affects the patients, but also their families who serve as the primary caregivers. Discovering novel therapeutic targets for stroke is crucial both from a quality of life perspective as well as from a health economic perspective. Exercise is known to promote neuroprotection in the context of stroke. Indeed, exercise induces the release of blood-borne factors that promote positive effects on the brain. Identifying the factors that mediate the positive effects of exercise after ischemic stroke is crucial for the quest for novel therapies. This approach will yield endogenous molecules that normally cross the blood brain barrier (BBB) and that can mimic the effects of exercise. In this minireview, we will discuss the roles of exercise factors released by the liver such as beta-hydroxybutyrate (DBHB), by the muscle such as lactate and irisin and by the bones such as osteocalcin. We will also address their therapeutic potential in the context of ischemic stroke.

Keywords:  BDNF; beta-hydroxybutyrate; exercise factors; irisin; lactate; osteocalcin; stroke

DOI:  https://doi.org/10.3389/fneur.2021.600365