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Both ageing and exercise training affect the neuromuscular junction (NMJ) structure. Morphological alterations in the NMJ have been considered to influence neuromuscular transmission and myofibre properties, but the direct link between the morphology and function has yet to be established. We measured the neuromuscular transmission, myofibre composition and NMJ structure of 5‐month‐old (young) and 24‐month‐old untrained (aged control) and trained (aged trained) mice. Aged trained mice were subjected to 2 months of endurance training before the measurement. Neuromuscular transmission was evaluated in vivo as the ratio of ankle plantar flexion torque evoked by the sciatic nerve stimulation to that by direct muscle stimulation. The torque ratio was significantly lower in aged mice than in young and aged trained mice at high‐frequency stimulations, showing a significant positive correlation with voluntary grip strength. The degree of pre‐ to post‐synaptic overlap of the NMJ was also significantly lower in aged mice and positively correlated with the torque ratio. We also found that the proportion of fast‐twitch fibres in the soleus muscle decreased with age, and that age‐related denervation occurred preferentially in fast‐twitch fibres. Age‐related denervation and a shift in myofibre composition were partially prevented by endurance training. These results suggest that age‐related deterioration of the NMJ structure impairs neuromuscular transmission and alters myofibre composition, but these alterations can be prevented by structural amelioration of NMJ with endurance training. Our findings highlight the importance of the NMJ as a major determinant of age‐related deterioration of skeletal muscles and the clinical significance of endurance training as a countermeasure. Key points: The neuromuscular junction (NMJ) plays an essential role in neuromuscular transmission and the maintenance of myofibre properties.We show that neuromuscular transmission is impaired with ageing but recovered by endurance training, which contributes to alterations in voluntary strength.Neuromuscular transmission is associated with the degree of pre‐ to post‐synaptic overlap of the NMJ.Age‐related denervation of fast‐twitch fibres and a shift in myofibre composition toward a slower phenotype are partially prevented by endurance training.Our study provides substantial evidence that age‐related and exercise‐induced alterations in neuromuscular transmission and myofibre properties are associated with morphological changes in the NMJ. [ABSTRACT FROM AUTHOR]

The relationship between mechanistic target of rapamycin complex 1 (mTORC1) activation after resistance exercise and acetylcholine receptor (AChR) subunit gene expression remains largely unknown. Therefore, we aimed to investigate the effect of electrical stimulation‐induced intense muscle contraction, which mimics acute resistance exercise, on the mRNA expression of AChR genes and the signalling pathways involved in neuromuscular junction (NMJ) maintenance, such as mTORC1 and muscle‐specific kinase (MuSK). The gastrocnemius muscle of male adult Sprague–Dawley rats was isometrically exercised. Upon completion of muscle contraction, the rats were euthanized in the early (after 0, 1, 3, 6 or 24 h) and late (after 48 or 72 h) recovery phases and the gastrocnemius muscles were removed. Non‐exercised control animals were euthanized in the basal state (control group). In the early recovery phase, Agrn gene expression increased whereas LRP4 decreased without any change in the protein and gene expression of AChR gene subunits. In the late recovery phase, Agrn, Musk, Chrnb1, Chrnd and Chrne gene expression were altered and agrin and MuSK protein expression increased. Moreover, mTORC1 and protein kinase B/Akt‐histone deacetylase 4 (HDAC) were activated in the early phase but not in the late recovery phase. Furthermore, rapamycin, an inhibitor of mTORC1, did not disturb changes in AChR subunit gene expression after muscle contraction. However, rapamycin addition slightly increased AChR gene expression, while insulin did not impact it in rat L6 myotube. These results suggest that changes in the AChR subunits after muscle contraction are independent of the rapamycin‐sensitive mTORC1 pathway. What is the central question of this study?Can muscle contraction‐induced activation of mechanistic target of rapamycin complex 1 (mTORC1) be linked to changes in acetylcholine receptor (AChR) gene expression and molecular signalling for maintaining neuromuscular junctions (NMJs)?What is the main finding and its importance?An acute high‐intensity muscle contraction dynamically changes AChR gene expression and muscle‐specific kinase (MuSK) signalling proteins at the late recovery phase of the contraction. Additionally, pharmacological inhibition of mTORC1 via rapamycin does not affect muscle contraction‐induced alterations in AChR genes. Our findings indicate that an acute high‐intensity muscle contraction induces changes in MuSK signalling and mTORC1‐independent changes in expression of AChR genes. [ABSTRACT FROM AUTHOR]

Ribosome biogenesis is an important regulator of skeletal muscle hypertrophy induced by repeated bouts of resistance exercise (RE). Hot-water immersion (HWI), a widely used post-exercise recovery strategy, activates the mechanistic target of rapamycin (mTOR) signaling, a key regulator of ribosome biogenesis in skeletal muscle. However, the effect of HWI on skeletal muscle ribosome biogenesis is not well understood. Here, we aimed to investigate the effects of HWI and post-exercise HWI on ribosome biogenesis using a rat RE model. Male Sprague-Dawley rats were randomly assigned to HWI and non-HWI groups. In both groups, the right leg was isometrically exercised using transcutaneous electrical stimulation, while the left leg was used as an internal non-RE control. Following RE, both limbs were immersed in hot water (41.2 ± 0.03°C) for 20 min under isoflurane anesthesia in the HWI group and the gastrocnemius muscles were sampled at 3- and 24-h post-exercise. HWI significantly increased mTOR signaling and c-Myc mRNA expression, whereas post-exercise HWI significantly increased transcription initiation factor-IA mRNA expression. However, neither HWI nor post-exercise HWI enhanced 45S pre-rRNA expression, ribosomal RNA, or ribosomal protein content. In addition, HWI tended to decrease 28S rRNA and 18S rRNA content, widely used markers of ribosome content. These results suggest that HWI as a post-exercise recovery is not effective in activating ribosome biogenesis. NEW & NOTEWORTHY: Ribosome biogenesis is crucial in resistance exercise (RE)-induced skeletal muscle hypertrophy. This study examined the effects of hot-water immersion (HWI) on ribosome biogenesis after RE. HWI and post-exercise HWI increased c-Myc and transcription initiation factor-IA mRNA but did not alter ribosomal RNA transcription or ribosomal protein content. HWI tended to decrease 28S and 18S ribosomal RNA. These findings suggest that HWI, as a recovery strategy, does not effectively promote ribosome biogenesis or muscle protein synthesis. [ABSTRACT FROM AUTHOR]

Background/Objectives: Monocarboxylate transporters (MCTs) comprise 14 known isoforms, with MCT1 being particularly important for lactate transport. Variations in lactate metabolism capacity and aerobic performance are associated with the T1470A polymorphism in MCT1. We aimed to investigate the frequency of the T1470A polymorphism and compare relevant physiological parameters among long-distance runners, wherein these parameters are fundamental to athletic performance. Methods: We included 158 Japanese long-distance runners (LD) and 649 individuals from the general Japanese population (CON). The frequency of the T1470A polymorphism was compared between these groups and across athletic levels using the chi-square test. Additionally, physiological data were collected from 57 long-distance runners, and respiratory gas measurements were obtained using the mixing-chamber method during a graded incremental exercise test. Results: We observed a significant difference between the LD and CON groups in the dominant model and between the sub-28 min group and 28 min or above group in the recessive model. As the competitive level increased, the frequency of the AA genotype also increased. When comparing physiological parameters between the AA genotype and T allele, subjects with the AA genotype showed significantly higher values for oxygen uptake at lactate threshold (p = 0.001), oxygen uptake at onset of blood lactate accumulation (p = 0.01), maximal oxygen uptake (p = 0.005), and maximal blood lactate concentration (p = 0.038). Conclusions: These results suggest that the AA genotype of the T1470A polymorphism of MCT1 is an effective genotype associated with athletic status and aerobic capacity in Japanese long-distance runners. [ABSTRACT FROM AUTHOR]

The greater muscle fiber cross-sectional area (CSA) is associated with greater skeletal muscle mass and strength, whereas muscle fiber atrophy is considered a major feature of sarcopenia. Muscle fiber size is a polygenic trait influenced by both environmental and genetic factors. However, the genetic variants underlying inter-individual differences in muscle fiber size remain largely unknown. The aim of our study was to determine whether 1535 genetic variants previously identified in a genome-wide association study of appendicular lean mass are associated with the CSA of fast-twitch muscle fibers (which better predict muscle strength) in the m. vastus lateralis of 148 physically active individuals (19 power-trained and 28 endurance-trained females, age 28.0 ± 1.1; 28 power-trained and 73 endurance-trained males, age 31.1 ± 0.8). Fifty-seven single-nucleotide polymorphisms (SNPs) were identified as having an association with muscle fiber size (p < 0.05). Of these 57 SNPs, 31 variants were also associated with handgrip strength in the UK Biobank cohort (n = 359,729). Furthermore, using East Asian and East European athletic (n = 731) and non-athletic (n = 515) cohorts, we identified 16 SNPs associated with athlete statuses (sprinter, wrestler, strength, and speed–strength athlete) and weightlifting performance. All SNPs had the same direction of association, i.e., the lean mass-increasing allele was positively associated with the CSA of muscle fibers, handgrip strength, weightlifting performance, and power athlete status. In conclusion, we identified 57 genetic variants associated with both appendicular lean mass and fast-twitch muscle fiber size of m. vastus lateralis that may, in part, contribute to a greater predisposition to power sports. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]