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Simple Summary: High-impact publications have reported both the beneficial and harmful effects of catecholamines on cancer hallmarks and outcomes—a contradiction that is underappreciated and poorly explained. Here, we aimed to investigate whether differences in adrenergic receptor isoform expression can explain different cancer hallmark responses to catecholamines, since cancer cells can vary greatly in the expressions of nine adrenergic receptors. For this purpose, we cultured two cancer cell lines that systematically differ in their adrenergic receptor expressions: A673 cells, which express α1D-, α2C-, β1-, and β3-adrenergic receptors, and RD sarcoma cells, which barely express any adrenergic receptors. The cells were treated with noradrenaline to elucidate the effects of noradrenaline exposure on cell proliferation, migration, and cAMP signaling. While the A673 cells responded to noradrenaline treatment with decreased cell numbers, cell proliferation and migration, and increased cAMP signaling, the RD cells did not respond to noradrenaline. Therefore, our findings indicate that the adrenergic receptor isoform expressions might indeed explain why cancers can respond differently to increases in catecholamine concentrations due to, e.g., a bout of exercise, psychosocial stress, surgery, or drugs such as β-blockers. Background: Exercise has beneficial effects on cancer and its treatment, but the underlying mechanisms are poorly understood. Some studies have linked the positive impact of exercise to catecholamine signaling. In contrast, cancer stress studies have typically reported that catecholamines worsen cancer hallmarks and outcomes. Here, we aimed to investigate whether adrenergic receptor isoform expression can explain the contradictory effects of catecholamines in cancer. Methods: We cultured two pediatric sarcoma cancer cell lines that either express (A673 cell line) or do not express (RD cell line) adrenergic receptors. The cells were treated with a 5× dilution series of noradrenaline to assess the effects of noradrenaline on cell numbers. After these dose-finding experiments, we treated both cancer cell lines with 60 μM noradrenaline to examine its effect on cell proliferation and migration and cAMP signaling. Results: Treatment with 60 μM noradrenaline significantly decreased the cell numbers by 61.89% ± 10.36 (p ≤ 0.001), decreased cell proliferation by 15.88% ± 6.76 (p ≤ 0.05), decreased cell migration after 24 h (p ≤ 0.001), and increased cAMP concentrations 38-fold (p ≤ 0.001) in the A673 cells, which express adrenergic receptors, but not in the RD cells, which do not express adrenergic receptors. Conclusions: Our results indicate, as a proof of principle, that the effects of catecholamines on cancer progression and metastasis might depend on the expressions of the nine adrenergic receptor isoforms. As cancers express adrenergic and other receptors differentially, this has implications for the response of cancers to exercise, stress, and medication and may help to further personalize cancer treatments. [ABSTRACT FROM AUTHOR]

Ageing, immobilization, sepsis or cachexia reduce muscle mass and function. The age-related loss, i.e. sarcopenia, contributes to frailty and results in a loss of mobility and autonomy in aging and disease. Affected individuals are often socially isolated, have a greater risk of metabolic disorders and psychosomatic problems. As a result, quality of life and life expectancy are affected. Immobilization and lack of adequate stimuli to the skeletal muscle seem to play a central part in these problems. To overcome them, resistance training (i.e., weightlifting) is an effective intervention. Despite the efficacy of resistance training for increasing muscle mass and function, this treatment is underused in clinical practice. We argue that this is due to a lack of a generally applicable methodology. To address this and related problems, we have formed the Network of Expertise for Immobilization-induced Muscle Disorders (KNIMS) to develop a potential algorithm for treating sarcopenia and other immobilization-related muscle disorders. An important aspect of the proposed method is that it is defined as a formal algorithm that consists of two stages. Stage A aims to recover bed-ridden patients' ability to stand by applying vibration-tilt table technology. Stage B aims at rehabilitating compromised gait, using a combination of squats, lunges and single leg raises. It is anticipated that this algorithm-based approach will enhance the ability for standardization and documentation, whilst reducing resource efforts at the same time, which will be equally useful to clinical practice and to clinical research. [ABSTRACT FROM AUTHOR]

The article discusses the potential of turning fat into muscle as an alternative to anti-obesity drugs like semaglutide. It highlights the effectiveness of GLP-1 receptor agonists in reducing body weight and introduces the concept of repartitioning drugs that stimulate muscle hypertrophy and reduce fat mass. The text suggests that interventions promoting global muscle hypertrophy may have anti-obesity and anti-diabetic effects, emphasizing the need for further research in this area to develop effective treatments for obesity and metabolic diseases. [Extracted from the article]

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]

Airborne respiratory aerosol particle transmission of pathogens such as severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), influenza, or rhinoviruses plays a major role in the spread of infectious diseases. The infection risk is increased during indoor exercise, as aerosol particle emission can increase by more than 100-fold from rest to maximal exercise. Earlier studies have investigated the effect of factors such as age, sex, and body mass index (BMI), but only at rest and without taking ventilation into account. Here, we report that during both rest and exercise, subjects aged 60 to 76 y emit on average more than twice as many aerosol particles per minute than subjects aged 20 to 39 y. In terms of volume, older subjects emit on average five times as much dry volume (i.e., the residue of dried aerosol particles) than younger subjects. There was no statistically significant effect of sex or BMI within the test group. Together, this suggests that aging of the lung and respiratory tract is associated with an increased generation of aerosol particles irrespective of ventilation. Our findings demonstrate that age and exercise increase aerosol particle emission. In contrast, sex or BMI only have minor effects. [ABSTRACT FROM AUTHOR]

Pathogens such as severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), influenza, and rhinoviruses are transmitted by airborne aerosol respiratory particles that are exhaled by infectious subjects. We have previously reported that the emission of aerosol particles increases on average 132-fold from rest to maximal endurance exercise. The aims of this study are to first measure aerosol particle emission during an isokinetic resistance exercise at 80% of the maximal voluntary contraction until exhaustion, second to compare aerosol particle emission during a typical spinning class session versus a three-set resistance training session. Finally, we then used this data to calculate the risk of infection during endurance and resistance exercise sessions with different mitigation strategies. During a set of isokinetic resistance exercise, aerosol particle emission increased 10-fold from 5,400 ± 1,200 particles/min at rest to 59,000 ± 69,900 particles/ min during a set of resistance exercise. We found that aerosol particle emission per minute is on average 4.9-times lower during a resistance training session than during a spinning class. Using this data, we determined that the simulated infection risk increase during an endurance exercise session was sixfold higher than during a resistance exercise session when assuming one infected participant in the class. Collectively, this data helps to select mitigation measures for indoor resistance and endurance exercise classes at times where the risk of aerosol-transmitted infectious disease with severe outcomes is high. [ABSTRACT FROM AUTHOR]

During exercise, there is an increase in amino acid (AA) oxidation accompanied by a depression in whole-body protein synthesis and an increase in protein breakdown. Leucine oxidation increases in proportion to energy expenditure, but the total contribution of BCAA to fuel provision during exercise is minor and insufficient to increase dietary protein requirements. When investigating the effects of AA on the control of muscle protein synthesis (MPS), we showed that increased availability of mixed AAs caused a rise in human MPS to about the same extent as complete meals. Leucine alone (and to some extent other essential, but not nonessential, AAs) can stimulate MPS for a short period, suggesting that leucine acts as a signal as well as a substrate. MPS stimulation by infused AAs shows tachyphylaxis, returning to basal rates after 2 h, possibly explaining why chronically elevated leucine delivery does not elevate MPS clinically. Increased availability of essential amino acids (EAAs) results in dose-related responses of MPS, but, in elderly subjects, there is blunted sensitivity and responsiveness associated with decreased total RNA and mRNA for signaling proteins and signaling activity. Increases of MPS due to EAAs are associated with elevation of signaling activity in the mammalian target of rapamycin (mTOR)/p70 ribosomal subunit S6 kinase eukaryotic initiation factor 4 binding protein 1 pathway, without requiring rises of plasma insulin availability above 10 [micro]U/mL. However, at insulin of KEY WORDS: * protein * fuel * protein turnover * muscle

Today, researchers, practitioners, and physicians measure the concentration of lactate during a graded exercise test to determine thresholds related to the maximal lactate steady state (maxLass) as a sensitive measure of endurance capacity. In the 1970s and 1980s, a group of Cologne-based researchers around Wildor Hollmann, Alois Mader, and Hermann Heck developed the methodology for systematic lactate testing and introduced a 4 mmol. L−1 lactate threshold. Later, they also developed the concept of the maxLass, and Mader designed a sophisticated mathematical model of human energy metabolism during exercise. Mader`s model simulates metabolic responses to exercise based on individual variables such as maximum oxygen uptake (VO2max) and the maximal rate of lactate formation (νLa.max). Mader’s model predicts that the νLa.max reduces the power at the anaerobic threshold and endurance performance but that a high νLa.max is required for events with high power outputs in elite athletes. Mader’s model also assumed before the millennium that the rate of fat oxidation is explained by the difference between glycolytic pyruvate synthesis and the actual rate of pyruvate oxidation which is consistent with current opinion. Mader’s model also simulated the VO2max slow component in the mid1980s. Unfortunately, several landmark studies by the Cologne group were only published in German, and as a result, contributions by the Cologne group are under-appreciated in the English-speaking world. This narrative review aims to introduce key contributions of the Cologne group to human metabolism research especially for readers who do not speak German. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine alterations of the metabolome in blood plasma in response to concentric-eccentric leg exercise performed at a simulated altitude of 3,500 m. To do so, we recruited 11 well-trained subjects and performed an untargeted metabolomics analysis of plasma samples obtained before, 20 min after as well as on day 8 after five sets of maximal, concentric-eccentric leg exercises that lasted 90 s each. We identified and annotated 115 metabolites through untargeted liquid chromatography-mass spectrometry metabolomics and used them to further calculate 20 sum/ratio of metabolites. A principal component analysis (PCA) revealed differences in-between the overall metabolome at rest and immediately after exercise. Interestingly, some systematic changes of relative metabolite concentrations still persisted on day 8 after exercise. The first two components of the PCA explained 34% of the relative concentrations of all identified metabolites analyzed together. A volcano plot indicates that 35 metabolites and two metabolite ratios were significantly changed directly after exercise, such as metabolites related to carbohydrate and TCA metabolism. Moreover, we observed alterations in the relative concentrations of amino acids (e.g., decreases of valine, leucine and increases in alanine) and purines (e.g., increases in hypoxanthine, xanthine and uric acid). In summary, high intensity concentric-eccentric exercise performed at simulated altitude systematically changed the blood metabolome in trained athletes directly after exercise and some relative metabolite concentrations were still changed on day 8. The importance of that persisting metabolic alterations on exercise performance should be studied further. [ABSTRACT FROM AUTHOR]

Resistance training promotes metabolic health and stimulates muscle hypertrophy, but the precise routes by which resistance exercise (RE) conveys these health benefits are largely unknown. Aim: To investigate how acute RE affects human skeletal muscle metabolism. Methods: We collected vastus lateralis biopsies from six healthy male untrained volunteers at rest, before the first of 13 RE training sessions, and 45 min after the first and last bouts of RE. Biopsies were analysed using untargeted mass spectrometry-based metabolomics. Results: We measured 617 metabolites covering a broad range of metabolic pathways. In the untrained state RE altered 33 metabolites, including increased 3-methylhistidine and N-lactoylvaline, suggesting increased protein breakdown, as well as metabolites linked to ATP (xanthosine) and NAD (N1-methyl-2-pyridone-5-carboxamide) metabolism; the bile acid chenodeoxycholate also increased in response to RE in muscle opposing previous findings in blood. Resistance training led to muscle hypertrophy, with slow type I and fast/intermediate type II muscle fibre diameter increasing by 10.7% and 10.4%, respectively. Comparison of post-exercise metabolite levels between trained and untrained state revealed alterations of 46 metabolites, including decreased N-acetylated ketogenic amino acids and increased beta-citrylglutamate which might support growth. Only five of the metabolites that changed after acute exercise in the untrained state were altered after chronic training, indicating that training induces multiple metabolic changes not directly related to the acute exercise response. Conclusion: The human skeletal muscle metabolome is sensitive towards acute RE in the trained and untrained states and reflects a broad range of adaptive processes in response to repeated stimulation. [ABSTRACT FROM AUTHOR]

Injuries, high altitude, and endurance exercise lead to hypoxic conditions in skeletal muscle and sometimes to hypoxia-induced local tissue damage. Thus, regenerative myoblasts/satellite cells are exposed to different levels and durations of partial oxygen pressure depending on the spatial distance from the blood vessels. To date, it is unclear how hypoxia affects myoblasts proliferation, differentiation, and particularly fusion with normoxic myoblasts. To study this, we investigated how 21% and 2% oxygen affects C2C12 myoblast morphology, proliferation, and myogenic differentiation and evaluated the fusion of normoxic- or hypoxic-preconditioned C2C12 cells in 21% or 2% oxygen in vitro. Out data show that the long-term hypoxic culture condition does not affect the proliferation of C2C12 cells but leads to rounder cells and reduced myotube formation when compared with myoblasts exposed to normoxia. However, when normoxic- and hypoxic-preconditioned myoblasts were differentiated together, the resultant myotubes were significantly larger than the control myotubes. Whole transcriptome sequencing analysis revealed several novel candidate genes that are differentially regulated during the differentiation under normoxia and hypoxia in mixed culture conditions and may thus be involved in the increase in myotube size. Taken together, oxygen-dependent adaption and interaction of myoblasts may represent a novel approach for the development of innovative therapeutic targets. [ABSTRACT FROM AUTHOR]

Simple Summary: Exercise can counteract some of the adverse effects of cancer and its treatment. Epidemiological and mechanistic data suggest that exercise can influence cancer hallmarks, survival, and recurrence. Our pilot study aimed to assess the feasibility and safety of a single bout of high-intensity interval training (HIIT) in childhood cancer patients. The predefined feasibility criteria included recruitment rate, acceptability, practicability, and data acquisition. Very strict inclusion criteria and surveillance guaranteed safety, and no severe adverse events occurred. Our HIIT protocol is applicable only in a small number of childhood cancer patients. Blood lactate concentrations and heart rates significantly increased after HIIT, indicating that the patients achieved the targeted high exercise intensity. In conclusion, our preliminary data suggest that HIIT is safe and feasible in a small number of childhood cancer patients who do not suffer from severe side effects of treatment. Additional exercise protocols should be developed for patients with pronounced cancer-related impairments and health restrictions. Low- and moderate-intensity exercise is safe and feasible during childhood cancer treatment. The feasibility of a bout of high-intensity interval training (HIIT) in this population has not been analyzed to date. Pediatric cancer patients aged between 6 and 18 years were selected based on clinical conditions to perform ten sets of 15 s HIIT (>90% of estimated maximal heart rate (HRmax)) and 1 min active recovery on a bicycle ergometer within the first three chemotherapy courses. We assessed safety and feasibility criteria and the following parameters: perceived exertion rate, heart rate, and lactate and adrenaline concentrations. Out of 212 eligible patients, 11 patients aged 13.9 ± 3.6 years (n = 7 ♂) with lymphoma, leukemia, rhabdomyosarcoma, nephroblastoma, and synovial sarcoma completed the bout of HIIT without serious adverse events. During exercise, patients reached a BORG value maxima of 16 ± 1.2, and their heart rates rose from 78 ± 17 beats per minute (bpm) at rest to 178 ± 12 bpm after exercise (90 ± 6% estimated HRmax). The power-to-weight ratio was 2 ± 0.5 W/kg (watt per kilogram). Blood lactate concentrations increased from 1.09 ± 0.50 mmol/L (millimole per liter) at rest to 5.05 ± 1.88 mmol/L post-exercise. Our preliminary data suggest that HIIT is applicable only in a small number of childhood cancer patients. Individually adapted exercise protocols for patients with multiple impairments are needed. [ABSTRACT FROM AUTHOR]