Coculture with Colon-26 cancer cells decreases the protein synthesis rate and shifts energy metabolism toward glycolysis dominance in C2C12 myotubes.

Cancer cachexia is the result of complex interorgan interactions initiated by cancer cells and changes in patient behavior such as decreased physical activity and energy intake. Therefore, it is crucial to distinguish between the direct and indirect effects of cancer cells on muscle mass regulation and bioenergetics to identify novel therapeutic targets. In this study, we investigated the direct effects of Colon-26 cancer cells on the molecular regulating machinery of muscle mass and its bioenergetics using a coculture system with C2C12 myotubes. Our results demonstrated that coculture with Colon-26 cells induced myotube atrophy and reduced skeletal muscle protein synthesis and its regulating mechanistic target of rapamycin complex 1 signal transduction. However, we did not observe any activating effects on protein degradation pathways including ubiquitin-proteasome and autophagy-lysosome systems. From a bioenergetic perspective, coculture with Colon-26 cells decreased the complex I-driven, but not complex II-driven, mitochondrial ATP production capacity, while increasing glycolytic enzyme activity and glycolytic metabolites, suggesting a shift in energy metabolism toward glycolysis dominance. Gene expression profiling by RNA sequencing showed that the increased activity of glycolytic enzymes was consistent with changes in gene expression. However, the decreased ATP production capacity of mitochondria was not in line with the gene expression. The potential direct interaction between cancer cells and skeletal muscle cells revealed in this study may contribute to a better fundamental understanding of the complex pathophysiology of cancer cachexia.NEW & NOTEWORTHY We explored the potential direct interplay between colon cancer cells (Colon-26) and skeletal muscle cells (C2C12 myotubes) employing a noncontact coculture experimental model. Our findings reveal that coculturing with Colon-26 cells substantially impairs the protein synthesis rate, concurrently instigating a metabolic shift toward glycolytic dominance in C2C12 myotubes. This research unveils critical insights into the intricate cellular cross talk underpinning the complex pathophysiology of cancer cachexia.

Alterations in neuromuscular junction morphology with ageing and endurance training modulate neuromuscular transmission and myofibre composition.

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.

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.

Dietary apple polyphenols enhance mitochondrial turnover and respiratory chain enzymes.

Previous studies have demonstrated the beneficial effects of apple polyphenol (AP) intake on muscle endurance. Since mitochondria are critical for muscle endurance, we investigated mitochondrial enzyme activity, biogenesis, degradation and protein quality control. Twenty-four Wistar rats were randomly fed a 5% AP diet (5% AP group, n = 8), a 0.5% AP diet (0.5% AP group, n = 8), or a control diet (control group, n = 8). After a 4-week feeding period, the expression level of peroxisome proliferator-activated receptor γ coactivator-1α, a mitochondrial biosynthetic factor, did not increase, whereas that of transcription factor EB, another regulator of mitochondrial synthesis, significantly increased. Moreover, the mitochondrial count did not differ significantly between the groups. In contrast, mitophagy-related protein levels were significantly increased. The enzymatic activities of mitochondrial respiratory chain complexes II, III and IV were significantly higher in the AP intake group than in the control group. We conclude that AP feeding increases the activity of respiratory chain complex enzymes in rat skeletal muscles. Moreover, mitochondrial biosynthesis and degradation may have increased in AP-treated rats. NEW FINDINGS: What is the central question of this study? Does the administration of apple polyphenols (AP) affect mitochondrial respiratory chain complex enzyme activity, biogenesis, degradation and protein quality control in rat skeletal muscles? What is the main finding and its importance? AP feeding increases respiratory chain complex enzyme activity in rat skeletal muscle. Moreover, AP administration increases transcription factor EB activation, and mitophagy may be enhanced to promote degradation of dysfunctional mitochondria, but mitochondrial protein quality control was not affected.

Hip flexion angle affects longitudinal muscle activity of the rectus femoris in leg extension exercise.

PURPOSE: We investigated the effect of the hip flexion angle (HFA) on the longitudinal muscle activity of the rectus femoris (RF) during leg extension exercise (LEE). METHODS: We conducted an acute study in a specific population. Nine male bodybuilders performed isotonic LEE using a leg extension machine at three different HFAs: 0°, 40°, and 80°. Participants extended their knees from 90° to 0° at each HFA setting for four sets of ten repetitions at 70% of the one-repetition maximum. The transverse relaxation time (T2) of the RF was measured before and after LEE using magnetic resonance imaging. We analyzed the rate of change in the T2 value in the proximal, middle, and distal regions of the RF. The subjective sensation of muscle contraction of the quadriceps was measured using a numerical rating scale (NRS) and compared with the T2 value which was the objective index. RESULTS: At 80°, the T2 value in the middle RF was lower than that in the distal RF (p < 0.05). The T2 values at 0° and 40° HFA were higher than those at 80° HFA in the proximal (p < 0.05, p < 0.01) and middle RF (p < 0.01, p < 0.01). The NRS scores were inconsistent with the objective index. CONCLUSION: These results suggest that the 40° HFA is practical for region-specific strengthening of the proximal RF, and subjective sensation alone as an indication of training may not activate the proximal RF. We conclude that activation of each longitudinal section of the RF is possible depending on the hip joint angle.

Arterial stiffness and physical fitness on cognitive function in community-dwelling middle-aged and older adults.

PURPOSE: This study examined whether decline in cognitive function is related to arterial stiffness and reduction in physical fitness in middle-aged and older adults. METHODS: A total of 1554 healthy middle-aged and older adults participated in this study. The trail making test parts-A (TMT-A) and B (TMT-B), brachial-ankle pulse wave velocity (baPWV), grip strength, the 30-s chair stand (CS-30) test, the 6-min walk (6MW) test, the 8-foot up-and-go (8UG) test and gait assessment were performed. Participants were classified into a middle-aged group (40-64 years; mean, 50.4 ± 0.2 years) or an older group (≥ 65 years; mean, 73.1 ± 0.5 years), as well as into three cognition (COG) groups (high, moderate, and low) based on median TMT-A and -B scores (high scores on both, either, or neither TMT-A and -B, respectively). RESULTS: The results revealed that baPWV was significantly lower in the high-than in the moderate- and low-COG groups in both middle-aged and older adults (P < 0.05). In addition, except for a few parameters (e.g., 6MW test in middle-aged adults), physical fitness was significantly higher in the high-than in the moderate- and low-COG groups in both middle-aged and older adults (P < 0.05). Multivariate regression analysis revealed that baPWV (P < 0.05) and some physical fitness indicators (grip strength, CS-30, and 8UG) were significantly independently associated with both TMT-A and -B in the middle-aged and older groups (P < 0.05). CONCLUSION: These results suggest that increased arterial stiffness and reduced physical fitness are associated with impaired cognitive function in middle-aged and older adults.

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.

Oxidative stress causes muscle structural alterations via p38 MAPK signaling in COPD mouse model.

INTRODUCTION: Sarcopenia is a complication of Chronic Obstructive Pulmonary Disease (COPD) that negatively affects physical activity and quality of life. However, the underlying mechanism by which COPD affects skeletal muscles remains to be elucidated. Therefore, we investigated the association between oxidative stress and structural alterations in muscles in elastase-induced emphysema mouse models. MATERIALS AND METHODS: Twelve-week-old male C57BL/6J mice were treated with either intratracheal porcine pancreatic elastase (PPE) dissolved in saline, or saline alone. The mice were euthanized 12 weeks after treatment, and the lungs and limb muscles were used for protein analysis of oxidative stress, p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway and muscle atrophy signaling pathway related with oxidative stress. Furthermore, C57BL/6J mice treated with PPE or saline were analyzed for the effects of oral administration of astaxanthin or p38 inhibitor. RESULTS: The weight of the soleus muscle, proportion of type I muscle fibers, and cross-sectional areas of muscle fibers in the PPE group were lower than those in the control group. Oxidative stress marker levels in the PPE group were elevated in skeletal muscles. The p38 MAPK signaling pathway was activated in the soleus muscles, leading to the activation of the ubiquitin-proteasome system and autophagy. Astaxanthin and p38 inhibitors attenuated alterations in muscle structure through the deactivation of the p38 MAPK signaling pathway. CONCLUSIONS: This study provides first evidence in COPD mouse model that oxidative stress trigger a series of muscle structural changes. Our findings suggest a novel target for sarcopenia in COPD.

The Effect of Online Low-intensity Exercise Training on Fitness and Cardiovascular Parameters.

Online exercise is undoubtedly useful and important; however, chronic adaptations to online exercise, particularly strength gain, muscle hypertrophy, and cardiovascular parameters, remain unclear. We investigated the effect of online exercise training using Zoom on fitness parameters compared with the same exercises supervised directly. In the present study, 34 subjects (age: 42.9±14.4 years) were included. Twenty-three subjects performed 8 weeks of body mass-based exercise training online using Zoom, and eleven subjects performed the same exercise supervised directly as the control group. The subjects performed low-load resistance exercises twice a week for 8 weeks for a total of 16 sessions. The sessions included 9 exercises: leg raises, squats, rear raises, shoulder presses, rowing, dips, lunges, Romanian dead lifts, and push-ups. Chair-stand, push-up, and sit-and-reach tests were performed on all subjects. Overall, the home exercise program effectively increased strength and muscle mass and decreased blood pressure and arterial stiffness, but there were no differences between the groups. Changes in chair-stand and sit-and-reach test results were higher in the control group than in the online group. Our results show that there is a similar training response to body mass-based training in both groups, even with virtual experiences using Zoom.

Low-Load Resistance Training to Volitional Failure Induces Muscle Hypertrophy Similar to Volume-Matched, Velocity Fatigue.

ABSTRACT: Terada, K, Kikuchi, N, Burt, D, Voisin, S, and Nakazato, K. Full title: Low-load resistance training to volitional failure induces muscle hypertrophy similar to volume-matched, velocity fatigue. J Strength Cond Res 36(6): 1576-1581, 2022-We investigated how resistance training (RT) to failure at low load affects acute responses and chronic muscle adaptations compared with low-load RT to velocity fatigue at equal work volume. Twenty-seven subjects performed 8 weeks of bench press twice weekly. Subjects were randomly assigned to one of 3 groups: low-load volitional failure (LVoF, n = 9), low-load velocity fatigue (LVeF, n = 8), and high-load (HL, n = 10). Resistance training comprised 3 sets to failure at 40% one repetition maximum (1RM) in the LVoF group, 3 sets to velocity fatigue (20% lifting velocity loss) at 40% 1RM in the LVeF group, and 3 sets of 8 repetitions at 80% 1RM in the HL group. We measured muscle strength, hypertrophy, endurance, and power at baseline and after the RT program. We also measured muscle swelling and blood lactate after each RT bout to investigate the acute response. There were no differences in total work volume between the LVoF and LVeF groups. Responses to RT were similar between LVoF and LVeF, whether looking at acute muscle swelling, increase in blood lactate, chronic hypertrophy, and strength gain. However, LVoF and LVeF RT triggered different responses to muscle function in comparison with HL training: LVoF and LVeF showed enhanced acute responses and greater chronic endurance gains, but lower chronic strength gains than HL. In conclusion, low-load RT to volitional failure induces muscle hypertrophy similar to volume-matched velocity fatigue.

Trabecular Bone Volume Is Reduced, With Deteriorated Microstructure, With Aging in a Rat Model of Duchenne Muscular Dystrophy.

We aimed to clarify the effect of aging on trabecular bone volume and trabecular bone microstructure in a rat model of Duchenne muscular dystrophy (DMD). Six rats each of wild type (WT) and DMD model at 15 weeks of age, and 4 rats each at 30 weeks of age, were analyzed by dual energy X-ray absorptiometry and by micro-CT for analysis of trabecular and cortical bone of the femur. Bone mineral density was significantly lower in the DMD group than in the WT group at both 15 and 30 weeks of age. Micro-CT showed that trabecular bone volume and number were not significantly different between the two groups at 15 weeks, but at 30 weeks both were significantly lower in the DMD group than in the WT group. Connectivity density and structure model index were not significantly different between the two groups at 15 weeks, but at 30 weeks they differed significantly. No significant differences between the WT and DMD groups in cortical thickness and cortical area were evident at both 15 and 30 weeks. In conclusion, trabecular bone volume is significantly reduced, with deteriorated microstructure, with aging in a rat model of DMD.

The ALDH2 rs671 polymorphism is associated with athletic status and muscle strength in a Japanese population.

Aldehyde dehydrogenase 2 (ALDH2) catalyses aldehyde species, including alcohol metabolites, mainly in the liver. We recently observed that ALDH2 is also expressed in skeletal muscle mitochondria; thus, we hypothesize that rs671 polymorphism-promoted functional loss of ALDH2 may induce deleterious effects in human skeletal muscle. We aimed to clarify the association of the ALDH2 rs671 polymorphism with muscle phenotypes and athletic capacity in a large Japanese cohort. A total of 3,055 subjects, comprising 1,714 athletes and 1,341 healthy control subjects (non-athletes), participated in this study. Non-athletes completed a questionnaire regarding their exercise habits, and were subjected to grip strength, 30-s chair stand, and 8-ft walking tests to assess muscle function. The ALDH2 GG, GA, and AA genotypes were detected at a frequency of 56%, 37%, and 7% among athletes, and of 54%, 37%, and 9% among non-athletes, respectively. The minor allele frequency was 25% in athletes and 28% in controls. Notably, ALDH2 genotype frequencies differed significantly between athletes and non-athletes (genotype: p = 0.048, allele: p = 0.021), with the AA genotype occurring at a significantly lower frequency among mixed-event athletes compared to non-athletes (p = 0.010). Furthermore, non-athletes who harboured GG and GA genotypes exhibited better muscle strength than those who carried the AA genotype (after adjustments for age, sex, body mass index, and exercise habits). The AA genotype and A allele of the ALDH2 rs671 polymorphism were associated with a reduced athletic capacity and poorer muscle phenotypes in the analysed Japanese cohort; thus, impaired ALDH2 activity may attenuate muscle function.

Genetic profile of sports climbing athletes from three different ethnicities.

This study aimed to investigate the ACTN3 R577X, ACE I/D, CKM rs8111989, and TRHR rs7832552 genotypes in climbers and controls in three ethnicities. The study consisted of 258 climbers (Japanese, n = 100; Polish, n = 128; Russian, n = 30) and 1151 controls (Japanese: n = 332, Polish: n = 635, Russian: n = 184). Genotyping results were analyzed using the TaqMan approach in Japanese and Polish subjects and HumanOmni1-Quad Bead Chips in Russian subjects. There were no significant differences in ACTN3 R577X and ACE I/D polymorphism distribution between climbers and controls in any ethnic cohort or model. The frequencies of the C allele in the CKM polymorphism and the T allele in the TRHR polymorphism were higher in climbers than in controls only in the Russian cohort (p = 0.045 and p = 0.039, respectively). The results of the meta-analysis on three cohorts showed that the frequency of XX + RX genotypes in the ACTN3 R577X polymorphism was significantly higher in climbers than that in the controls (p = 0.01). The X allele of the ACTN3 R577X polymorphism was associated with sport climbing status, as assessed using a meta-analysis of climbers across three different ethnicities.

c-Myc overexpression increases ribosome biogenesis and protein synthesis independent of mTORC1 activation in mouse skeletal muscle.

High-intensity muscle contractions (HiMCs) are known to increase c-Myc expression that is known to stimulate ribosome biogenesis and protein synthesis in most cells. However, although c-Myc mRNA transcription and c-Myc mRNA translation have been shown to be upregulated following resistance exercise concomitantly with increased ribosome biogenesis, this connection has not been tested directly. We investigated the effect of adeno-associated virus (AAV)-mediated c-Myc overexpression, with or without fasting or percutaneous electrical stimulation-induced HiMC, on ribosome biogenesis and protein synthesis in adult mouse skeletal muscles. AAV-mediated overexpression of c-Myc in mouse skeletal muscles for 2 wk increased the DNA polymerase subunit POL1 mRNA, 45S-pre-rRNA, total RNA, and muscle protein synthesis without altering mechanistic target of rapamycin complex 1 (mTORC1) signaling under both ad libitum and fasted conditions. RNA-sequencing (RNA-seq) analyses revealed that c-Myc overexpression mainly regulated ribosome biogenesis-related biological processes. The protein synthesis response to c-Myc overexpression mirrored the response with HiMC. No additional effect of combining c-Myc overexpression and HiMC was observed. Our results suggest that c-Myc overexpression is sufficient to stimulate skeletal muscle ribosome biogenesis and protein synthesis without activation of mTORC1. Therefore, the HiMC-induced increase in c-Myc may contribute to ribosome biogenesis and increased protein synthesis following HiMC.NEW & NOTEWORTHY Resistance exercise is known to increase c-Myc expression, which is known to stimulate ribosome biogenesis and protein synthesis in a variety of cells. However, whether the increase in c-Myc stimulates ribosome biogenesis and protein synthesis in skeletal muscles remains unknown. We found that c-Myc overexpression is sufficient to stimulate skeletal muscle ribosome biogenesis and protein synthesis without activation of mTORC1.

Repeated bouts of resistance exercise in rats alter mechanistic target of rapamycin complex 1 activity and ribosomal capacity but not muscle protein synthesis.

NEW FINDINGS: What is the central question of this study? Is muscle protein synthesis (MPS) additionally activated following exercise when ribosomal capacity is increased after repeated bouts of resistance exercise (RE)? What is the main finding and its importance? Skeletal muscles with increased ribosome content through repeated RE bouts showed sufficient activation of MPS with lower mechanistic target of rapamycin complex 1 signalling. Thus, repeated bouts of RE possibly change the translational capacity and efficiency to optimize translation activation following RE. ABSTRACT: Resistance exercise (RE) activates ribosome biogenesis and increases ribosome content in skeletal muscles. However, it is unclear whether the increase in ribosome content subsequently causes an increase in RE-induced activation of muscle protein synthesis (MPS). Thus, this study aimed to investigate the relationship between ribosome content and MPS after exercise using a rat RE model. Male Sprague-Dawley rats were categorized into three groups (n = 6 for each group): sedentary (SED) and RE trained with one bout (1B) or three bouts (3B). The RE stimulus was applied to the right gastrocnemius muscle by transcutaneous electrical stimulation under isoflurane anaesthesia. The 3B group underwent stimulation every other day. Our results revealed that 6 h after the last bout of RE, muscles in the 3B group showed an increase in total RNA and 18S+28S rRNA content per muscle weight compared with the SED and 1B groups. In both the 1B and 3B groups, MPS, estimated by puromycin incorporation in proteins, was higher than that in the SED group 6 h after exercise; however, no significant difference was observed between the 1B and 3B groups. In the 1B and 3B groups, phosphorylated p70S6K at Thr-389 increased, indicating mechanistic target of rapamycin complex 1 (mTORC1) activity. p70S6K phosphorylation level was lower in the 3B group than in the 1B group. Finally, protein synthesis per ribosome (indicator of translation efficiency) was lower in the 3B group than in the 1B group. Thus, three bouts of RE changed the ribosome content and mTORC1 activation, but not the degree of RE-induced global MPS activation.

Eccentric exercise causes delayed sensory nerve conduction velocity but no repeated bout effect in the flexor pollicis brevis muscles.

PURPOSE: This study was aimed at investigating the effect of eccentric contractions (ECCs) of flexor pollicis brevis muscles (FPBMs) on motor and sensory nerve functions as well as the ipsilateral repeated bout effect (IL-RBE) and contralateral (CL)-RBE of motor and sensory nerve conduction velocities following ECCs. METHODS: Thirty-two young healthy men (age: 19.6 ± 0.2 years, height: 173.2 ± 1.2 cm, body mass: 69.7 ± 1.9 kg) performed two bouts of ECCs. During the first ECCs bout (ECCs-1), all participants performed 100 ECCs with 1 hand; for the second bout, 3 groups (2 weeks [W]: n = 11, 4W: n = 10, 8W: n = 11) performed ECCs with both hands 2, 4, or 8 weeks after ECCs-1. The maximal voluntary isometric contraction (MVC), range of motion (ROM), visual analog scale for pain (VAS), motor and sensory nerve conduction velocities were measured before, immediately after, and 1, 2, 3, and 5 days after ECCs. RESULTS: ECCs-1 decreased the MVC, limited the ROM, developed VAS, and decreased the motor and sensory nerve conduction velocities compared to non-exercise hand (p < 0.05). The repeated bout effect was observed in the ROM for IL-RBE in 2W and 4W, VAS for IL-RBE in 2 W, and ROM and VAS for CL-RBE in 2W (p < 0.05). However, RBEs of MVC and motor and sensory nerve conduction velocities were not observed, and no differences were confirmed depending on the interval. CONCLUSION: In the present study, ECCs of the FPBM caused a sensory nerve dysfunction, while IL- or CL-RBE was not observed.

Association between MCT1 T1470A polymorphism and climbing status in Polish and Japanese climbers.

Sport climbing will become an official event at the 2020 Tokyo Olympics; it is a popular wilderness sport among athletes and amateurs. Our previous study suggested that the T1470A polymorphism (rs1049434) of the monocarboxylate transporter 1 (MCT1) gene is associated with athletic performance and physiological phenotypes. The purpose of this study was to investigate the frequency of MCT1 T1470A polymorphism in Polish and Japanese climbers using a case-control study. Our sample consisted of 226 climbers (Japanese: n = 100, 64 male and 36 female; Polish: n = 126, 97 male and 29 female) and 1028 non-athletic controls (Japanese, n = 407; Polish = 621) who were genotyped for the MCT1 T1470A polymorphism (rs1049434) using the TaqMan SNP genotyping assay or restriction enzyme. The frequency of the TT genotype and T allele was significantly higher in climbers than in controls among the Polish subjects (genotype: p = 0.030, allele: p = 0.010); however, there were no significant differences in the genotype and allelic frequencies between the Japanese climbers and controls (genotype: p = 0.968; allele: p = 0.803). Our results suggested that the frequency of the T allele (TT+TA genotype) in the MCT1 T1470A polymorphism is over-represented in Polish climbers but not in Japanese climbers. In addition, the frequency of the T allele and TT genotype in Polish lead climbers is higher than that in controls.

Electrically stimulated contractile activity-induced transcriptomic responses and metabolic remodeling in C2C12 myotubes: twitch vs. tetanic contractions.

The contraction of myotubes using electrical pulse stimulation is a research tool used to mimic muscle contractile activity and exercise in rodents and humans. Most protocols employed in previous work used low-frequency twitch contractions. However, high-frequency tetanus contractions that are more physiologically relevant to muscle contractions in vivo are poorly characterized. In this report, the similarities and differences in acute responses and chronic adaptations with different contractile modes using twitches (2 Hz, continuous, 3 h) and tetanus (66 Hz, on: 5 s/off: 5 s, 3 h) were investigated. RNA sequencing-based transcriptome analysis and subsequent bioinformatics analysis suggest that tetanus may promote bioenergetic remodeling rather than twitch. Based on in silico analyses, metabolic remodeling after three contractile sessions of twitch and tetanus were investigated. Although twitch and tetanus had no significant effect on glycolysis, both types of contraction upregulated glucose oxidation capacity. Both twitch and tetanus qualitatively caused mitochondrial adaptations (increased content, respiratory chain enzyme activity, and respiratory function). The magnitude of adaptation was much greater under tetanus conditions. Our findings indicate that the contraction of myotubes by tetanus may be a useful experimental model, especially in the study of metabolic adaptations in C2C12 myotubes.

Acetaldehyde dehydrogenase 2 deficiency increases mitochondrial reactive oxygen species emission and induces mitochondrial protease Omi/HtrA2 in skeletal muscle.

Acetaldehyde dehydrogenase 2 (ALDH2) is an enzyme involved in redox homeostasis as well as the detoxification process in alcohol metabolism. Nearly 8% of the world's population have an inactivating mutation in the ALDH2 gene. However, the expression patterns and specific functions of ALDH2 in skeletal muscles are still unclear. Herein, we report that ALDH2 is expressed in skeletal muscle and is localized to the mitochondrial fraction. Oxidative muscles had a higher amount of ALDH2 protein than glycolytic muscles. We next comprehensively investigated whether ALDH2 knockout in mice induces mitochondrial adaptations in gastrocnemius muscle (for example, content, enzymatic activity, respiratory function, supercomplex formation, and functional networking). We found that ALDH2 deficiency resulted in partial mitochondrial dysfunction in gastrocnemius muscle because it increased mitochondrial reactive oxygen species (ROS) emission (2',7'-dichlorofluorescein and MitoSOX oxidation rate during respiration) and the frequency of regional mitochondrial depolarization. Moreover, we determined whether ALDH2 deficiency and the related mitochondrial dysfunction trigger mitochondrial stress and quality control responses in gastrocnemius muscle (for example, mitophagy markers, dynamics, and the unfolded protein response). We found that ALDH2 deficiency upregulated the mitochondrial serine protease Omi/HtrA2 (a marker of the activation of a branch of the mitochondrial unfolded protein response). In summary, ALDH2 deficiency leads to greater mitochondrial ROS production, but homeostasis can be maintained via an appropriate stress response.

Repeated stretch-shortening contraction of the triceps surae attenuates muscle atrophy and liver dysfunction in a rat model of inflammation.

NEW FINDINGS: What is the central question of this study? Is stretch-shortening contraction effective to attenuate skeletal muscle atrophy and hepatic dysfunction in a rat model of peptidoglycan-polysaccharide (PG-PS)-induced inflammation (PG-PS rat)? What are the main findings and their importance? Stretch-shortening contraction attenuates skeletal muscle atrophy in the trained leg and increases circulating interleukin-10 in PG-PS rats. Stretch-shortening contraction also ameliorates liver dysfunction in PG-PS rats, possibly via increased blood interleukin-10. These findings are important because they suggest that stretch-shortening contraction is effective to maintain liver function in addition to exercised skeletal muscle mass. ABSTRACT: Stretch-shortening contraction (SSC) is an effective modality to improve skeletal muscle mass. However, the beneficial effects of SSC in the presence of chronic inflammation remain unclear. Here, we imposed five SSC sessions unilaterally on the triceps surae in young female Lewis rats. Rats were injected with vehicle or peptidoglycan-polysaccharide (PG-PS) to induce long-lasting inflammation. The PG-PS reduced gastrocnemius muscle mass in both legs, but that of the SSC-trained leg was significantly greater than that of the contralateral leg. Circulating pro-inflammatory cytokines, such as IL-1ß, were significantly increased by PG-PS injection, even if carrying out SSC. The circulating anti-inflammatory cytokine IL-10 increased with SSC in both healthy and inflammatory conditions. Stretch-shortening contraction also prevented increases in serum aspartate aminotransferase activity and plasma free phenylalanine concentration induced by PG-PS, in comparison to the control resistance exercise consisting of isometric contractions. Moreover, aspartate aminotransferase and phenylalanine concentrations demonstrated a significant and negative correlation with IL-10/IL-1ß values (r = -0.61, P = 0.017, and r = -0.66, P = 0.008, respectively). These results suggest that SSC training is effective to reduce both muscle atrophy and the hepatic dysfunction induced by PG-PS, mediated, at least in part, through an increase in circulating IL-10.