bims-exemet 2021-08-29 papers

Issue of 2021–08–29
six papers selected by
Javier Botella Ruiz, Victoria University

Physiol Rep. 2021 Aug;9(16): e15016

Voluntary exercise prevents abnormal muscle mitochondrial morphology in cancer cachexia mice.

Yu Kitaoka, Mitsunori Miyazaki, Shin Kikuchi.

This study aimed to examine the effects of voluntary wheel running on cancer cachexia-induced mitochondrial alterations in mouse skeletal muscle. Mice bearing colon 26 adenocarcinoma (C26) were used as a model of cancer cachexia. C26 mice showed a lower gastrocnemius and plantaris muscle weight, but 4 weeks of voluntary exercise rescued these changes. Further, voluntary exercise attenuated observed declines in the levels of oxidative phosphorylation proteins and activities of citrate synthase and cytochrome c oxidase in the skeletal muscle of C26 mice. Among mitochondrial morphology regulatory proteins, mitofusin 2 (Mfn2) and dynamin-related protein 1 (Drp1) were decreased in the skeletal muscle of C26 mice, but exercise resulted in similar improvements as seen in markers of mitochondrial content. In isolated mitochondria, 4-hydroxynonenal and protein carbonyls were elevated in C26 mice, but exercise blunted the increases in these markers of oxidative stress. In addition, electron microscopy revealed that exercise alleviated the observed increase in the percentage of damaged mitochondria in C26 mice. These results suggest that voluntary exercise effectively counteracts mitochondrial dysfunction to mitigate muscle loss in cachexia.

Keywords: cancer cachexia; mitochondria; oxidative stress; skeletal muscle; voluntary exercise

DOI: https://doi.org/10.14814/phy2.15016

Front Genet. 2021 ;12 652497

Regular, Intense Exercise Training as a Healthy Aging Lifestyle Strategy: Preventing DNA Damage, Telomere Shortening and Adverse DNA Methylation Changes Over a Lifetime.

Maha Sellami, Nicola Bragazzi, Mohammad Shoaib Prince, Joshua Denham, Mohamed Elrayess.

Exercise training is one of the few therapeutic interventions that improves health span by delaying the onset of age-related diseases and preventing early death. The length of telomeres, the 5'-TTAGGG n -3' tandem repeats at the ends of mammalian chromosomes, is one of the main indicators of biological age. Telomeres undergo shortening with each cellular division. This subsequently leads to alterations in the expression of several genes that encode vital proteins with critical functions in many tissues throughout the body, and ultimately impacts cardiovascular, immune and muscle physiology. The sub-telomeric DNA is comprised of heavily methylated, heterochromatin. Methylation and histone acetylation are two of the most well-studied examples of the epigenetic modifications that occur on histone proteins. DNA methylation is the type of epigenetic modification that alters gene expression without modifying gene sequence. Although diet, genetic predisposition and a healthy lifestyle seem to alter DNA methylation and telomere length (TL), recent evidence suggests that training status or physical fitness are some of the major factors that control DNA structural modifications. In fact, TL is positively associated with cardiorespiratory fitness, physical activity level (sedentary, active, moderately trained, or elite) and training intensity, but is shorter in over-trained athletes. Similarly, somatic cells are vulnerable to exercise-induced epigenetic modification, including DNA methylation. Exercise-training load, however, depends on intensity and volume (duration and frequency). Training load-dependent responses in genomic profiles could underpin the discordant physiological and physical responses to exercise. In the current review, we will discuss the role of various forms of exercise training in the regulation of DNA damage, TL and DNA methylation status in humans, to provide an update on the influence exercise training has on biological aging.

Keywords: epigenetic clock; epigenetics; gene; oxidative stress; physical activity; skeletal muscle; telomerase

DOI: https://doi.org/10.3389/fgene.2021.652497

FASEB J. 2021 09;35(9): e21864

Resistance training rejuvenates the mitochondrial methylome in aged human skeletal muscle.

Bradley A Ruple, Joshua S Godwin, Paulo H C Mesquita, Shelby C Osburn, Christopher G Vann, Donald A Lamb, Casey L Sexton, Darren G Candow, Scott C Forbes, Andrew D Frugé, Andreas N Kavazis, Kaelin C Young, Robert A Seaborne, Adam P Sharples, Michael D Roberts.

Resistance training (RT) dynamically alters the skeletal muscle nuclear DNA methylome. However, no study has examined if RT affects the mitochondrial DNA (mtDNA) methylome. Herein, ten older, Caucasian untrained males (65 ± 7 y.o.) performed six weeks of full-body RT (twice weekly). Body composition and knee extensor torque were assessed prior to and 72 h following the last RT session. Vastus lateralis (VL) biopsies were also obtained. VL DNA was subjected to reduced representation bisulfite sequencing providing excellent coverage across the ~16-kilobase mtDNA methylome (254 CpG sites). Biochemical assays were also performed, and older male data were compared to younger trained males (22 ± 2 y.o., n = 7, n = 6 Caucasian & n = 1 African American). RT increased whole-body lean tissue mass (p = .017), VL thickness (p = .012), and knee extensor torque (p = .029) in older males. RT also affected the mtDNA methylome, as 63% (159/254) of the CpG sites demonstrated reduced methylation (p < .05). Several mtDNA sites presented a more "youthful" signature in older males after RT in comparison to younger males. The 1.12 kilobase mtDNA D-loop/control region, which regulates replication and transcription, possessed enriched hypomethylation in older males following RT. Enhanced expression of mitochondrial H- and L-strand genes and complex III/IV protein levels were also observed (p < .05). While limited to a shorter-term intervention, this is the first evidence showing that RT alters the mtDNA methylome in skeletal muscle. Observed methylome alterations may enhance mitochondrial transcription, and RT evokes mitochondrial methylome profiles to mimic younger men. The significance of these findings relative to broader RT-induced epigenetic changes needs to be elucidated.

Keywords: aging; methylation; mitochondrial DNA; resistance training

DOI: https://doi.org/10.1096/fj.202100873RR

Front Sports Act Living. 2021 ;3 719434

Under the Hood: Skeletal Muscle Determinants of Endurance Performance.

Stephan van der Zwaard, Franck Brocherie, Richard T Jaspers.

In the past decades, researchers have extensively studied (elite) athletes' physiological responses to understand how to maximize their endurance performance. In endurance sports, whole-body measurements such as the maximal oxygen consumption, lactate threshold, and efficiency/economy play a key role in performance. Although these determinants are known to interact, it has also been demonstrated that athletes rarely excel in all three. The leading question is how athletes reach exceptional values in one or all of these determinants to optimize their endurance performance, and how such performance can be explained by (combinations of) underlying physiological determinants. In this review, we advance on Joyner and Coyle's conceptual framework of endurance performance, by integrating a meta-analysis of the interrelationships, and corresponding effect sizes between endurance performance and its key physiological determinants at the macroscopic (whole-body) and the microscopic level (muscle tissue, i.e., muscle fiber oxidative capacity, oxygen supply, muscle fiber size, and fiber type). Moreover, we discuss how these physiological determinants can be improved by training and what potential physiological challenges endurance athletes may face when trying to maximize their performance. This review highlights that integrative assessment of skeletal muscle determinants points toward efficient type-I fibers with a high mitochondrial oxidative capacity and strongly encourages well-adjusted capillarization and myoglobin concentrations to accommodate the required oxygen flux during endurance performance, especially in large muscle fibers. Optimisation of endurance performance requires careful design of training interventions that fine tune modulation of exercise intensity, frequency and duration, and particularly periodisation with respect to the skeletal muscle determinants.

Keywords: V̇O2max; aerobic performance; hypertrophy; metabolism; mitochondria; muscle fiber type; oxygen transport; training

DOI: https://doi.org/10.3389/fspor.2021.719434

Proc Natl Acad Sci U S A. 2021 Aug 31. pii: e2102895118. [Epub ahead of print]118(35):

Identification of a KLF5-dependent program and drug development for skeletal muscle atrophy.

Lin Liu, Hiroyuki Koike, Takehito Ono, Shinichiro Hayashi, Fujimi Kudo, Atsushi Kaneda, Hiroyuki Kagechika, Ichiro Manabe, Tomoki Nakashima, Yumiko Oishi.

Skeletal muscle atrophy is caused by various conditions, including aging, disuse related to a sedentary lifestyle and lack of physical activity, and cachexia. Our insufficient understanding of the molecular mechanism underlying muscle atrophy limits the targets for the development of effective pharmacologic treatments and preventions. Here, we identified Krüppel-like factor 5 (KLF5), a zinc-finger transcription factor, as a key mediator of the early muscle atrophy program. KLF5 was up-regulated in atrophying myotubes as an early response to dexamethasone or simulated microgravity in vitro. Skeletal muscle-selective deletion of Klf5 significantly attenuated muscle atrophy induced by mechanical unloading in mice. Transcriptome- and genome-wide chromatin accessibility analyses revealed that KLF5 regulates atrophy-related programs, including metabolic changes and E3-ubiquitin ligase-mediated proteolysis, in coordination with Foxo1. The synthetic retinoic acid receptor agonist Am80, a KLF5 inhibitor, suppressed both dexamethasone- and microgravity-induced muscle atrophy in vitro and oral Am80 ameliorated disuse- and dexamethasone-induced atrophy in mice. Moreover, in three independent sets of transcriptomic data from human skeletal muscle, KLF5 expression significantly increased with age and the presence of sarcopenia and correlated positively with the expression of the atrophy-related ubiquitin ligase genes FBXO32 and TRIM63 These findings demonstrate that KLF5 is a key transcriptional regulator mediating muscle atrophy and that pharmacological intervention with Am80 is a potentially preventive treatment.

Keywords: KLF; RAR ligand; muscle atrophy

DOI: https://doi.org/10.1073/pnas.2102895118