bims-exemet 2021-04-18 papers

Issue of 2021–04–18
five papers selected by
Javier Botella Ruiz, Victoria University

Sci Adv. 2021 Apr;pii: eabf2856. [Epub ahead of print]7(16):

Histamine H1 and H2 receptors are essential transducers of the integrative exercise training response in humans.

Thibaux Van der Stede, Laura Blancquaert, Flore Stassen, Inge Everaert, Ruud Van Thienen, Chris Vervaet, Lasse Gliemann, Ylva Hellsten, Wim Derave.

Exercise training is a powerful strategy to prevent and combat cardiovascular and metabolic diseases, although the integrative nature of the training-induced adaptations is not completely understood. We show that chronic blockade of histamine H1/H2 receptors led to marked impairments of microvascular and mitochondrial adaptations to interval training in humans. Consequently, functional adaptations in exercise capacity, whole-body glycemic control, and vascular function were blunted. Furthermore, the sustained elevation of muscle perfusion after acute interval exercise was severely reduced when H1/H2 receptors were pharmaceutically blocked. Our work suggests that histamine H1/H2 receptors are important transducers of the integrative exercise training response in humans, potentially related to regulation of optimal post-exercise muscle perfusion. These findings add to our understanding of how skeletal muscle and the cardiovascular system adapt to exercise training, knowledge that will help us further unravel and develop the exercise-is-medicine concept.

DOI: https://doi.org/10.1126/sciadv.abf2856

Redox Biol. 2021 Apr 05. pii: S2213-2317(21)00114-2. [Epub ahead of print]43 101966

Skeletal muscle-specific Keap1 disruption modulates fatty acid utilization and enhances exercise capacity in female mice.

Takahiro Onoki, Yoshihiro Izumi, Masatomo Takahashi, Shohei Murakami, Daisuke Matsumaru, Nao Ohta, Sisca Meida Wati, Nozomi Hatanaka, Fumiki Katsuoka, Mitsuharu Okutsu, Yutaka Yabe, Yoshihiro Hagiwara, Makoto Kanzaki, Takeshi Bamba, Eiji Itoi, Hozumi Motohashi.

Skeletal muscle health is important for the prevention of various age-related diseases. The loss of skeletal muscle mass, which is known as sarcopenia, underlies physical disability, poor quality of life and chronic diseases in elderly people. The transcription factor NRF2 plays important roles in the regulation of the cellular defense against oxidative stress, as well as the metabolism and mitochondrial activity. To determine the contribution of skeletal muscle NRF2 to exercise capacity, we conducted skeletal muscle-specific inhibition of KEAP1, which is a negative regulator of NRF2, and examined the cell-autonomous and non-cell-autonomous effects of NRF2 pathway activation in skeletal muscles. We found that NRF2 activation in skeletal muscles increased slow oxidative muscle fiber type and improved exercise endurance capacity in female mice. We also observed that female mice with NRF2 pathway activation in their skeletal muscles exhibited enhanced exercise-induced mobilization and β-oxidation of fatty acids. These results indicate that NRF2 activation in skeletal muscles promotes communication with adipose tissues via humoral and/or neuronal signaling and facilitates the utilization of fatty acids as an energy source, resulting in increased mitochondrial activity and efficient energy production during exercise, which leads to improved exercise endurance.

Keywords: Beta-oxidation; Exercise; Fatty acid; KEAP1-NRF2 system; Skeletal muscle

DOI: https://doi.org/10.1016/j.redox.2021.101966

Am J Physiol Endocrinol Metab. 2021 Apr 12.

Combined effects of a ketogenic diet and exercise training alter mitochondrial and peroxisomal substrate oxidative capacity in skeletal muscle.

Tai-Yu Huang, Melissa A Linden, Scott E Fuller, Felicia R Goldsmith, Jacob Simon, Heidi M Batdorf, Matthew C Scott, Nabil M Essajee, John M Brown, Robert C Noland.

Ketogenic diets (KD) are reported to improve body weight, fat mass, and exercise performance in humans. Unfortunately, most rodent studies have used a low-protein KD, which does not recapitulate diets used by humans. Since skeletal muscle plays a critical role in responding to macronutrient perturbations induced by diet and exercise, the purpose of this study was to test if a normal-protein KD (NPKD) impacts shifts in skeletal muscle substrate oxidative capacity in response to exercise training (ExTr). A high fat, carbohydrate-deficient NPKD (16.1% protein, 83.9% fat, 0% carbohydrate) was given to C57BL/6J male mice for 6 weeks, while controls received a low fat diet with similar protein (15.9% protein, 11.9% fat, 72.2% carbohydrate). On week four of the diet, mice began treadmill training 5 days/week, 60 min/day for 3 weeks. NPKD-fed mice increased body weight and fat mass, while ExTr negated a continued rise in adiposity. ExTr increased intramuscular glycogen, while the NPKD increased intramuscular triglycerides. Neither the NPKD nor ExTr alone altered mitochondrial content; however, in combination, the NPKD-ExTr group showed increases in PGC-1α, as well as markers of mitochondrial fission and fusion. Pyruvate oxidative capacity was unchanged by either intervention, while ExTr increased leucine oxidation in NPKD-fed mice. Lipid metabolism pathways had the most notable changes as the NPKD and ExTr interventions both enhanced mitochondrial and peroxisomal lipid oxidation and many adaptations were additive or synergistic. Overall these results suggest a combination of a NPKD and ExTr induces additive and/or synergistic adaptations in skeletal muscle oxidative capacity.

Keywords: exercise; ketogenic diet; mitochondria; peroxisomal; substrate oxidation

DOI: https://doi.org/10.1152/ajpendo.00410.2020

EMBO J. 2021 Apr 13. e106491

A necessary role of DNMT3A in endurance exercise by suppressing ALDH1L1-mediated oxidative stress.

Sneha Damal Villivalam, Scott M Ebert, Hee Woong Lim, Jinse Kim, Dongjoo You, Byung Chul Jung, Hector H Palacios, Tabitha Tcheau, Christopher M Adams, Sona Kang.

Exercise can alter the skeletal muscle DNA methylome, yet little is known about the role of the DNA methylation machinery in exercise capacity. Here, we show that DNMT3A expression in oxidative red muscle increases greatly following a bout of endurance exercise. Muscle-specific Dnmt3a knockout mice have reduced tolerance to endurance exercise, accompanied by reduction in oxidative capacity and mitochondrial respiration. Moreover, Dnmt3a-deficient muscle overproduces reactive oxygen species (ROS), the major contributors to muscle dysfunction. Mechanistically, we show that DNMT3A suppresses the Aldh1l1 transcription by binding to its promoter region, altering its epigenetic profile. Forced expression of ALDH1L1 elevates NADPH levels, which results in overproduction of ROS by the action of NADPH oxidase complex, ultimately resulting in mitochondrial defects in myotubes. Thus, inhibition of ALDH1L1 pathway can rescue oxidative stress and mitochondrial dysfunction from Dnmt3a deficiency in myotubes. Finally, we show that in vivo knockdown of Aldh1l1 largely rescues exercise intolerance in Dnmt3a-deficient mice. Together, we establish that DNMT3A in skeletal muscle plays a pivotal role in endurance exercise by controlling intracellular oxidative stress.

Keywords: DNA methylation; exercise; oxidative stress

DOI: https://doi.org/10.15252/embj.2020106491