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We aimed to compare the effects of periodic resistance training (RT) and continuous RT on muscle strength and size. Fifty‐five healthy, untrained participants (age 32 ± 5 years) were randomized to periodic (PRT, n = 20 completed the study, 45% females) or continuous (CRT, n = 22 completed the study, 45% females) groups. PRT completed a 10‐week RT, a 10‐week detraining, and a second identical 10‐week RT. CRT began with a 10‐week non‐RT, followed by a 20‐week RT. RT included twice‐weekly supervised whole‐body RT sessions. Leg press (LP) and biceps curl (BC) one repetition maximum (1RM), countermovement jump (CMJ) height, muscle cross‐sectional area (CSA) of vastus lateralis (VL), and biceps brachii (BB) using ultrasound imaging were measured twice at the beginning and every fifth week during the intervention. Both groups increased (p < 0.001) 1RM in LP and BC, CSA in VL and BB, and CMJ height with no differences between the groups. In PRT, 1RM in LP and BC, CSA in VL and BB, and CMJ height decreased during detraining (p < 0.05). During the first 5 weeks of retraining in PRT, increases in LP 1RM, and VL and BB CSA were greater than in CRT during Weeks 10–15 of their CRT (p < 0.01). PRT and CTR ended up in similar postintervention adaptations, as decreased muscle strength and size during detraining in PRT regained rapidly during retraining. Our results therefore suggest that trainees should not be too concerned about occasional short‐term training breaks in their daily lives when it comes to lifelong strength training. Trial Registration:ClinicalTrials.gov identifier: NCT05553769 [ABSTRACT FROM AUTHOR]

Exercise-like electrical pulse stimulation (EL-EPS) of myotubes mimics many key physiological changes induced by in vivo exercise. Besides enabling intracellular research, EL-EPS allows to study secreted factors, including muscle-specific microRNAs (myomiRs) carried in extracellular vesicles (EVs). These factors can participate in contraction-induced intercellular cross talk and may mediate the health benefits of exercise. However, the current knowledge of these responses, especially under variable nutritional conditions, is limited. We investigated the effects of EL-EPS on C2C12 myotube transcriptome in high- and low-glucose conditions by messenger RNA sequencing, while the expression of EV-carried miRNAs was analyzed by small RNA sequencing and RT-qPCR. We show that higher glucose availability augmented contraction-induced transcriptional changes and that the majority of the differentially expressed genes were upregulated. Furthermore, based on the pathway analyses, processes related to contractility and cytokine/inflammatory responses were upregulated. In addition, we report that EL-EPS increased packing of miR-1-3p into EVs independent of glucose availability. Together our findings suggest that in vitro EL-EPS is a usable tool not only to study contraction-induced intracellular mechanisms but also extracellular responses. The distinct transcriptional changes observed under variable nutritional conditions emphasize the importance of careful consideration of media composition in future exercise-mimicking studies. NEW & NOTEWORTHY The present study examined for the first time the effects of exercise-like electrical pulse stimulation administered under distinct nutritional conditions on 1) the transcriptome of the C2C12 myotubes and 2) their media containing extracellular vesicle-carried microRNAs. We report that higher glucose availability augmented transcriptional responses related especially to contractility and cytokine/inflammatory pathways. Agreeing with in vivo studies, we show that the packing of exercise-responsive miR-1-3p was increased in the extracellular vesicles in response to myotube contractions. [ABSTRACT FROM AUTHOR]

Cells use glycolytic intermediates for anabolism, e.g., via the serine synthesis and pentose phosphate pathways. However, we still understand poorly how these metabolic pathways contribute to skeletal muscle cell biomass generation. The first aim of this study was therefore to identify enzymes that limit protein synthesis, myotube size, and proliferation in skeletal muscle cells. We inhibited key enzymes of glycolysis, the pentose phosphate pathway, and the serine synthesis pathway to evaluate their importance in C2C12 myotube protein synthesis. Based on the results of this first screen, we then focused on the serine synthesis pathway enzyme phosphoglycerate dehydrogenase (PHGDH). We used two different PHGDH inhibitors and mouse C2C12 and human primary muscle cells to study the importance and function of PHGDH. Both myoblasts and myotubes incorporated glucose-derived carbon into proteins, RNA, and lipids, and we showed that PHGDH is essential in these processes. PHGDH inhibition decreased protein synthesis, myotube size, and myoblast proliferation without cytotoxic effects. The decreased protein synthesis in response to PHGDH inhibition appears to occur mainly mechanistic target of rapamycin complex 1 (mTORC1)-dependently, as was evident from experiments with insulin-like growth factor 1 and rapamycin. Further metabolomics analyses revealed that PHGDH inhibition accelerated glycolysis and altered amino acid, nucleotide, and lipid metabolism. Finally, we found that supplementing an antioxidant and redox modulator, N-acetylcysteine, partially rescued the decreased protein synthesis and mTORC1 signaling during PHGDH inhibition. The data suggest that PHGDH activity is critical for skeletal muscle cell biomass generation from glucose and that it regulates protein synthesis and mTORC1 signaling. NEW & NOTEWORTHY: The use of glycolytic intermediates for anabolism was demonstrated in both myoblasts and myotubes, which incorporate glucose-derived carbon into proteins, RNA, and lipids. We identify phosphoglycerate dehydrogenase (PHGDH) as a critical enzyme in those processes and also for muscle cell hypertrophy, proliferation, protein synthesis, and mTORC1 signaling. Our results thus suggest that PHGDH in skeletal muscle is more than just a serine-synthesizing enzyme. [ABSTRACT FROM AUTHOR]

Cachexia is a debilitating wasting syndrome and highly prevalent comorbidity in cancer patients. It manifests especially with energy and mitochondrial metabolism aberrations that promote tissue wasting. We recently identified nicotinamide adenine dinucleotide (NAD+) loss to associate with muscle mitochondrial dysfunction in cancer hosts. In this study we confirm that depletion of NAD+ and downregulation of Nrk2, an NAD+ biosynthetic enzyme, are common features of severe cachexia in different mouse models. Testing NAD+ repletion therapy in cachectic mice reveals that NAD+ precursor, vitamin B3 niacin, efficiently corrects tissue NAD+ levels, improves mitochondrial metabolism and ameliorates cancer- and chemotherapy-induced cachexia. In a clinical setting, we show that muscle NRK2 is downregulated in cancer patients. The low expression of NRK2 correlates with metabolic abnormalities underscoring the significance of NAD+ in the pathophysiology of human cancer cachexia. Overall, our results propose NAD+ metabolism as a therapy target for cachectic cancer patients. The loss of nicotinamide adenine dinucleotide is reported to be associated with muscle mitochondrial dysfunction in murine cancer models. Here the authors show that niacin supplementation improves mitochondrial metabolism and reduces muscle wasting in mouse models of cachexia. [ABSTRACT FROM AUTHOR]