Monocarboxylate transporter 4 deficiency enhances high-intensity interval training-induced metabolic adaptations in skeletal muscle.

High-intensity exercise stimulates glycolysis, subsequently leading to elevated lactate production within skeletal muscle. While lactate produced within the muscle is predominantly released into the circulation via the monocarboxylate transporter 4 (MCT4), recent research underscores lactate's function as an intercellular and intertissue signalling molecule. However, its specific intracellular roles within muscle cells remains less defined. In this study, our objective was to elucidate the effects of increased intramuscular lactate accumulation on skeletal muscle adaptation to training. To achieve this, we developed MCT4 knockout mice and confirmed that a lack of MCT4 indeed results in pronounced lactate accumulation in skeletal muscle during high-intensity exercise. A key finding was the significant enhancement in endurance exercise capacity at high intensities when MCT4 deficiency was paired with high-intensity interval training (HIIT). Furthermore, metabolic adaptations supportive of this enhanced exercise capacity were evident with the combination of MCT4 deficiency and HIIT. Specifically, we observed a substantial uptick in the activity of glycolytic enzymes, notably hexokinase, glycogen phosphorylase and pyruvate kinase. The mitochondria also exhibited heightened pyruvate oxidation capabilities, as evidenced by an increase in oxygen consumption when pyruvate served as the substrate. This mitochondrial adaptation was further substantiated by elevated pyruvate dehydrogenase activity, increased activity of isocitrate dehydrogenase - the rate-limiting enzyme in the TCA cycle - and enhanced function of cytochrome c oxidase, pivotal to the electron transport chain. Our findings provide new insights into the physiological consequences of lactate accumulation in skeletal muscle during high-intensity exercises, deepening our grasp of the molecular intricacies underpinning exercise adaptation. KEY POINTS: We pioneered a unique line of monocarboxylate transporter 4 (MCT4) knockout mice specifically tailored to the ICR strain, an optimal background for high-intensity exercise studies. A deficiency in MCT4 exacerbates the accumulation of lactate in skeletal muscle during high-intensity exercise. Pairing MCT4 deficiency with high-intensity interval training (HIIT) results in a synergistic boost in high-intensity exercise capacity, observable both at the organismal level (via a treadmill running test) and at the muscle tissue level (through an ex vivo muscle contractile function test). Coordinating MCT4 deficiency with HIIT enhances both the glycolytic enzyme activities and mitochondrial capacity to oxidize pyruvate.

Effect of different types of muscle activity on the gene and protein expression of ALDH family members in C57BL/6J mouse skeletal muscle.

Aldehyde dehydrogenase (ALDH) is an enzyme that detoxifies aldehydes and is primarily involved in alcohol metabolism. Recently, we have shown that ALDH also plays an important role in skeletal muscle homeostasis. To better understand the role of ALDH in skeletal muscle, it is necessary to clarify the adaptability of ALDH. In this study, we examined the effects of endurance training, compensatory hypertrophy by synergist ablation (SA), and denervation-induced atrophy on gene expression and protein levels of selected ALDH isoforms in skeletal muscle. Ten-week-old C57BL/6J mice were subjected to each intervention, and the plantaris muscle was collected. Gene expression levels of Aldh1a1 were decreased by SA and denervation, but ALDH1A1 protein levels were not affected. Protein levels of ALDH1B1 increased after chronic endurance training, SA, and denervation interventions. However, the increase in Aldh1b1 gene expression was observed only after SA. The gene expression of Aldh2 was decreased after SA, but ALDH2 protein levels remained unchanged. Denervation increased both the Aldh2 gene and ALDH2 protein levels. Taken together, each isoform of ALDH undergoes unique quantitative adaptations in skeletal muscle under different conditions.

Aldehyde dehydrogenase 2 deficiency promotes skeletal muscle atrophy in aged mice.

Aldehyde dehydrogenase 2 (ALDH2) detoxifies acetaldehyde produced from ethanol. A missense single nucleotide polymorphism (SNP) rs671 in ALDH2 exhibits a dominant-negative form of the ALDH2 protein. Nearly 40% of people in East Asia carry an inactive ALDH2*2 mutation. Previous studies reported that ALDH2*2 is associated with increased risk of several diseases. In this study, we examined the effect of ALDH2 deficiency on age-related muscle atrophy and its underlying mechanisms. We found that ALDH2 deficiency promotes age-related loss of muscle fiber cross-sectional areas, especially in oxidative fibers. Furthermore, ALDH2 deficiency exacerbated age-related accumulation of 4-hydroxy-2-nonenal (4-HNE), a marker of oxidative stress in the gastrocnemius muscle. Similarly, mitochondrial reactive oxygen species (ROS) production increased in aged ALDH2-knockout mice, indicating that ALDH2 deficiency induced mitochondrial dysfunction. In summary, ALDH2 deficiency promotes age-related muscle loss, especially in oxidative fibers, which may be associated with an increased accumulation of oxidative stress via mitochondrial dysfunction.

Effects of endurance training on the expression of host proteins involved in SARS-CoV-2 cell entry in C57BL/6J mouse.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is threatening people's lives and impacting their health. It is still unclear whether people engaged in physical activity are at an increased risk of SARS-CoV-2 infection and severe forms of COVID-19. In order to provide data to help answer this question, we, therefore, investigated the effects of endurance training on the levels of host proteins involved in SARS-CoV-2 infection in mice. Eight-week-old C57BL/6J mice were subjected to treadmill running (17-25 m/min, 60-90 min, 5 sessions/week, 8 weeks). After the intervention, the levels of angiotensin-converting enzyme 2 (ACE2; host receptor for SARS-CoV-2), transmembrane protease serine 2 (TMPRSS2; host protease priming fusion of SARS-CoV-2 to host cell membranes), FURIN (host protease that promotes binding of SARS-CoV-2 to host receptors), and Neuropilin-1 (host coreceptor for SARS-CoV-2) were measured in 10 organs that SARS-CoV-2 can infect (larynx, trachea, lung, heart, jejunum, ileum, colon, liver, kidney, and testis). Six organs (heart, lung, jejunum, liver, trachea, and ileum) showed changes in the levels of at least one of the proteins. Endurance training increased ACE2 levels in heart (+66.4%), lung (+37.1%), jejunum (+24.7%) and liver (+27.4%), and FURIN in liver (+17.9%) tissue. In contrast, endurance training decreased Neuropilin-1 levels in liver (-39.7%), trachea (-41.2%), and ileum (-39.7%), and TMPRSS2 in lung (-11.3%). Taken together, endurance training altered the levels of host proteins involved in SARS-CoV-2 cell entry in an organ-dependent manner.