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1.
Low-dose fentanyl does not alter muscle sympathetic nerve activity, blood pressure, or tolerance during progressive central hypovolemia.
Huang, M, Watso, JC, Belval, LN, Cimino, FA, Fischer, M, Jarrard, CP, Hendrix, JM, Laborde, CH, Crandall, CG
American journal of physiology. Regulatory, integrative and comparative physiology. 2022;(1):R55-R63
Abstract
Hemorrhage is a leading cause of battlefield and civilian trauma deaths. Several pain medications, including fentanyl, are recommended for use in the prehospital (i.e., field setting) for a hemorrhaging solider. However, it is unknown whether fentanyl impairs arterial blood pressure (BP) regulation, which would compromise hemorrhagic tolerance. Thus, the purpose of this study was to test the hypothesis that an analgesic dose of fentanyl impairs hemorrhagic tolerance in conscious humans. Twenty-eight volunteers (13 females) participated in this double-blinded, randomized, placebo-controlled trial. We conducted a presyncopal limited progressive lower body negative pressure test (LBNP; a validated model to simulate hemorrhage) following intravenous administration of fentanyl (75 µg) or placebo (saline). We quantified tolerance as a cumulative stress index (mmHg·min), which was compared between trials using a paired, two-tailed t test. We also compared muscle sympathetic nerve activity (MSNA; microneurography) and beat-to-beat BP (photoplethysmography) during the LBNP test using a mixed effects model [time (LBNP stage) × trial]. LBNP tolerance was not different between trials (fentanyl: 647 ± 386 vs. placebo: 676 ± 295 mmHg·min, P = 0.61, Cohen's d = 0.08). Increases in MSNA burst frequency (time: P < 0.01, trial: P = 0.29, interaction: P = 0.94) and reductions in mean BP (time: P < 0.01, trial: P = 0.50, interaction: P = 0.16) during LBNP were not different between trials. These data, the first to be obtained in conscious humans, demonstrate that administration of an analgesic dose of fentanyl does not alter MSNA or BP during profound central hypovolemia, nor does it impair tolerance to this simulated hemorrhagic insult.
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Therapeutic approaches to preserve the musculature in Duchenne Muscular Dystrophy: The importance of the secondary therapies.
Angelini, G, Mura, G, Messina, G
Experimental cell research. 2022;(2):112968
Abstract
Muscular dystrophies (MDs) are heterogeneous diseases, characterized by primary wasting of skeletal muscle, which in severe cases, such as Duchenne Muscular Dystrophy (DMD), leads to wheelchair dependency, respiratory failure, and premature death. Research is ongoing to develop efficacious therapies, particularly for DMD. Most of the efforts, currently focusing on correcting or restoring the primary defect of MDs, are based on gene-addition, exon-skipping, stop codon read-through, and genome-editing. Although promising, most of them revealed several practical limitations. Shared knowledge in the field is that, in order to be really successful, any therapeutic approach has to rely on spared functional muscle tissue, restricting the number of patients eligible for clinical trials to the youngest and less compromised individuals. In line with this, many therapeutic strategies aim to preserve muscle tissue and function. This Review outlines the most interesting and recent studies addressing the secondary outcomes of DMD and how to better deliver the therapeutic agents. In the future, the effective treatment of DMD will likely require combinations of therapies addressing both the primary genetic defect and its consequences.
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A new paradigm in sarcopenia: Cognitive impairment caused by imbalanced myokine secretion and vascular dysfunction.
Jo, D, Yoon, G, Kim, OY, Song, J
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2022;:112636
Abstract
Sarcopenia characterized by reduced skeletal muscle mass and decreased muscle strength is increasing in prevalence globally. The pathophysiology of sarcopenia is related to various factors including hormonal imbalance, increased intracellular oxidative stress, reduction of food intake, advanced age, low body mass index, and low physical activity. Recently, sarcopenia has been reported to be associated with cognitive decline, and the common risk factors between sarcopenia and memory loss were observed in cohort studies. Many researchers suggested that the prevalence of sarcopenia is associated with vascular disorder, such as atherosclerosis and alteration of intracellular mechanisms caused by changes in myokine secretion. We herein review the emerging evidence on the strong link between cognitive impairment and sarcopenia, focusing on myokine secretion and vascular dysfunction, and provide an understanding of the relevant mechanisms and crucial determinants in cognitive decline caused by sarcopenia.
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Association of the gut microbiota and fecal short-chain fatty acids with skeletal muscle mass and strength in children.
Chen, F, Li, Q, Chen, Y, Wei, Y, Liang, J, Song, Y, Shi, L, Wang, J, Mao, L, Zhang, B, et al
FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2022;(1):e22109
Abstract
We aimed to investigate whether the gut microbiota and fecal short-chain fatty acids (SCFAs) are associated with skeletal muscle mass and strength in healthy Chinese children aged 6-9 years. In this study, 412 children were enrolled. 16S rRNA gene sequencing was used to characterize the gut microbiota compositions. Fecal SCFAs were quantified using high-performance liquid chromatography. Dual X-ray absorptiometry was used to measure the total body lean soft tissue mass (TSM), total body fat mass (TBF), appendicular skeletal muscle mass (ASM), and appendicular fat mass (AFM). TSM/height2 (TSMI), ASM/height2 (ASMI), TSM/weight (TSMR), ASM/weight (ASMR), and the ratio of TSM/TBF and ASM/AFM were calculated. Handgrip strength (HGS) was measured using the Jamar® Plus+ Hand Dynamometer. A multiple regression analysis after adjustment for covariates and multiple test correction showed some operational taxonomic units in partial least squares models identified by Multivariate methods with Unbiased Variable selection analysis such as genera of Faecalibacterium, Lachnospira, Lachnospiraceae_ND3007_group, and Lachnospiraceae_UCG-004 were positively correlated with at least one measure of TSM, TSMI, ASM, ASMI, and ASMI Z-score (β: 0.103-0.143, pFDR : .008-.032) but negatively correlated with at least one measure of TSMR, TSM/TBF, ASMR, ASM/AFM, and ASMR Z-score (β: -0.185 to 0.124, pFDR = .008-.045). Children with higher fecal butyric acid, acetic acid, and total SCFA levels exhibited higher TSM, ASM, TSMI, ASMI, and ASMI Z-score and lower TSM/TBF, ASM/AFM, TSMR, ASMR, and ASMR Z-score. However, after additional adjustment for TBF or body mass index, only the associations for Faecalitalea and Pyramidobacter still existed. Mediation analysis suggested that total body fat significantly mediated 66.3%-95.3% of the estimated association of microbiota and SCFAs with TSM, ASM, and ASMI Z-score. Our results suggest that the associations of gut microbiota and SCFAs with skeletal muscle quality in children may largely depend upon on total body fat content.
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Muscle weakness as an additional criterion for grading sarcopenia-related prognosis in patients with cancer.
Cereda, E, Tancredi, R, Klersy, C, Lobascio, F, Crotti, S, Masi, S, Cappello, S, Stobäus, N, Tank, M, Cutti, S, et al
Cancer medicine. 2022;(2):308-316
Abstract
BACKGROUND Low muscle strength has been pointed out as a key characteristic of sarcopenia, but the prognostic significance of muscle function next to reduced skeletal muscle mass (SMM) in patients with cancer has been scantily investigated. METHODS Data on muscle strength by handgrip (HG) dynamometry and total-body SMM estimated by bioelectrical impedance analysis (BIA) of Italian and German patients with cancer observed prospectively until death or censoring were analysed (N = 1076). Patients were stratified in four risk categories based on low HG (<10th percentiles of age and gender-specific normative values) and low total-body SMM according to SMM index cutoffs (<10.75 and <6.75 kg/m2 in men and women, respectively). RESULTS During a median follow-up of 58 months [25th-75th percentile, 37-60], 566 patients had died. Patients presenting low HG in combination or not with low SMM were characterised by shorter median survival (12.7 vs. 27.2 months, respectively; p < 0.001) compared to those with low SMM/normal HG and normal SMM/normal HG (>60 months for both). After adjusting for sex, age, body mass index and percentage of weight loss, disease's stage, performance status and type of cancer, compared to reference category (normal HG and SMM; N = 210) the hazard ratios were: low SMM/normal HG (N = 342), 0.83 [95% confidence interval, CI, 0.67-1.02] (p = 0.073); normal SMM/low HG (N = 158), 1.19 [95% CI, 1.07-1.32] (p = 0.002); low SMM/low HG (N = 366), 1.39 [95% CI, 1.27-1.53] (p < 0.001). CONCLUSIONS Muscle weakness was found to be a more powerful predictor of survival than BIA-estimated SMM and should be considered as an additional key feature of sarcopenia in patients with cancer.
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6.
Dietary palmitate and oleate differently modulate insulin sensitivity in human skeletal muscle.
Sarabhai, T, Koliaki, C, Mastrototaro, L, Kahl, S, Pesta, D, Apostolopoulou, M, Wolkersdorfer, M, Bönner, AC, Bobrov, P, Markgraf, DF, et al
Diabetologia. 2022;(2):301-314
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Abstract
AIMS/HYPOTHESIS Energy-dense nutrition generally induces insulin resistance, but dietary composition may differently affect glucose metabolism. This study investigated initial effects of monounsaturated vs saturated lipid meals on basal and insulin-stimulated myocellular glucose metabolism and insulin signalling. METHODS In a randomised crossover study, 16 lean metabolically healthy volunteers received single meals containing safflower oil (SAF), palm oil (PAL) or vehicle (VCL). Whole-body glucose metabolism was assessed from glucose disposal (Rd) before and during hyperinsulinaemic-euglycaemic clamps with D-[6,6-2H2]glucose. In serial skeletal muscle biopsies, subcellular lipid metabolites and insulin signalling were measured before and after meals. RESULTS SAF and PAL raised plasma oleate, but only PAL significantly increased plasma palmitate concentrations. SAF and PAL increased myocellular diacylglycerol and activated protein kinase C (PKC) isoform θ (p < 0.05) but only PAL activated PKCɛ. Moreover, PAL led to increased myocellular ceramides along with stimulated PKCζ translocation (p < 0.05 vs SAF). During clamp, SAF and PAL both decreased insulin-stimulated Rd (p < 0.05 vs VCL), but non-oxidative glucose disposal was lower after PAL compared with SAF (p < 0.05). Muscle serine1101-phosphorylation of IRS-1 was increased upon SAF and PAL consumption (p < 0.05), whereas PAL decreased serine473-phosphorylation of Akt more than SAF (p < 0.05). CONCLUSIONS/INTERPRETATION Lipid-induced myocellular insulin resistance is likely more pronounced with palmitate than with oleate and is associated with PKC isoforms activation and inhibitory insulin signalling. TRIAL REGISTRATION ClinicalTrials.gov .NCT01736202. FUNDING German Federal Ministry of Health, Ministry of Culture and Science of the State North Rhine-Westphalia, German Federal Ministry of Education and Research, European Regional Development Fund, German Research Foundation, German Center for Diabetes Research.
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Fasting-Mimicking-Diet does not reduce skeletal muscle function in healthy young adults: a randomized control trial.
Nardon, M, Venturelli, M, Ruzzante, F, Longo, VD, Bertucco, M
European journal of applied physiology. 2022;(3):651-661
Abstract
PURPOSE The aim of this study was to evaluate the short- and long-term effects of the Fasting-Mimicking-Diet (FMD) intervention on neuromuscular parameters of force production in healthy young men. METHODS Twenty-four physically active men completed the study. Participants were randomly assigned to Fasting-Mimicking (FMD) or Normal Diet (ND) and asked to follow three cycles of dietary intervention. Neuromuscular parameters of force production during maximal voluntary isometric contractions (MVCs) with the leg extensors muscles and anthropometrics were measured at baseline (T0), at the end of the first cycle (T1), and 7-10 days after the 3rd cycle of the nutritional intervention (T2). The study was registered on Clinicaltrials.gov (No. NCT04476615). RESULTS There was a significant decrease in body mass at T1 for FMD (- 2.6 kg, ∆ from baseline, on average; p < 0.05) but not in ND (- 0.1 kg;). Neuromuscular parameters of force production, muscle volume, and MVC torque did not change or differ between groups across visits. Results were similar even when parameters were normalized by muscle volume. CONCLUSION The consumption of FMD in a group of young healthy male subjects showed to be feasible, and it did not affect neuromuscular parameters of force production. The results suggest that FMD could be safely adopted by strength athletes without detrimental effects on force and muscle volume. Further research in clinical population at risk of muscle mass loss, such as elderly and obese subjects with sarcopenia, is warranted.
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Long-Term Evolution of Malnutrition and Loss of Muscle Strength after COVID-19: A Major and Neglected Component of Long COVID-19.
Gérard, M, Mahmutovic, M, Malgras, A, Michot, N, Scheyer, N, Jaussaud, R, Nguyen-Thi, PL, Quilliot, D
Nutrients. 2021;(11)
Abstract
UNLABELLED Post-acute consequences of COVID-19, also termed long COVID, include signs and symptoms persisting for more than 12 weeks with prolonged multisystem involvement; most often, however, malnutrition is ignored. METHOD The objective was to analyze persistent symptoms, nutritional status, the evolution of muscle strength and performance status (PS) at 6 months post-discharge in a cohort of COVID-19 survivors. RESULTS Of 549 consecutive patients hospitalized for COVID-19 between 1 March and 29 April 2020, 23.7% died and 288 patients were at home at D30 post-discharge. At this date, 136 of them (47.2%) presented persistent malnutrition, a significant decrease in muscle strength or a PS ≥ 2. These patients received dietary counseling, nutritional supplementation, adapted physical activity guidance or physiotherapy assistance, or were admitted to post-care facilities. At 6 months post-discharge, 91.0% of the 136 patients (n = 119) were evaluated and 36.0% had persistent malnutrition, 14.3% complained of a significant decrease in muscle strength and 14.9% had a performance status > 2. Obesity was more frequent in patients with impairment than in those without (52.8% vs. 31.0%; p = 0.0071), with these patients being admitted more frequently to ICUs (50.9% vs. 31.3%; p = 0.010). Among those with persistent symptoms, 10% had psychiatric co-morbidities (mood disorders, anxiety, or post-traumatic stress syndrome), 7.6% had prolonged pneumological symptoms and 4.2% had neurological symptoms. CONCLUSIONS Obese subjects as well as patients who have stayed in intensive care have a higher risk of functional loss or undernutrition 6 months after a severe COVID infection. Malnutrition and loss of muscle strength should be considered in the clinical assessment of these patients.
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Mild intermittent hypoxia exposure induces metabolic and molecular adaptations in men with obesity.
van Meijel, RLJ, Vogel, MAA, Jocken, JWE, Vliex, LMM, Smeets, JSJ, Hoebers, N, Hoeks, J, Essers, Y, Schoffelen, PFM, Sell, H, et al
Molecular metabolism. 2021;:101287
Abstract
OBJECTIVE Recent studies suggest that hypoxia exposure may improve glucose homeostasis, but well-controlled human studies are lacking. We hypothesized that mild intermittent hypoxia (MIH) exposure decreases tissue oxygen partial pressure (pO2) and induces metabolic improvements in people who are overweight/obese. METHODS In a randomized, controlled, single-blind crossover study, 12 men who were overweight/obese were exposed to MIH (15 % O2, 3 × 2 h/day) or normoxia (21 % O2) for 7 consecutive days. Adipose tissue (AT) and skeletal muscle (SM) pO2, fasting/postprandial substrate metabolism, tissue-specific insulin sensitivity, SM oxidative capacity, and AT and SM gene/protein expression were determined. Furthermore, primary human myotubes and adipocytes were exposed to oxygen levels mimicking the hypoxic and normoxic AT and SM microenvironments. RESULTS MIH decreased systemic oxygen saturation (92.0 ± 0.5 % vs 97.1 ± 0.3, p < 0.001, respectively), AT pO2 (21.0 ± 2.3 vs 36.5 ± 1.5 mmHg, p < 0.001, respectively), and SM pO2 (9.5 ± 2.2 vs 15.4 ± 2.4 mmHg, p = 0.002, respectively) compared to normoxia. In addition, MIH increased glycolytic metabolism compared to normoxia, reflected by enhanced fasting and postprandial carbohydrate oxidation (pAUC = 0.002) and elevated plasma lactate concentrations (pAUC = 0.005). Mechanistically, hypoxia exposure increased insulin-independent glucose uptake compared to standard laboratory conditions (~50 %, p < 0.001) and physiological normoxia (~25 %, p = 0.019) through AMP-activated protein kinase in primary human myotubes but not in primary human adipocytes. MIH upregulated inflammatory/metabolic pathways and downregulated extracellular matrix-related pathways in AT but did not alter systemic inflammatory markers and SM oxidative capacity. MIH exposure did not induce significant alterations in AT (p = 0.120), hepatic (p = 0.132) and SM (p = 0.722) insulin sensitivity. CONCLUSIONS Our findings demonstrate for the first time that 7-day MIH reduces AT and SM pO2, evokes a shift toward glycolytic metabolism, and induces adaptations in AT and SM but does not induce alterations in tissue-specific insulin sensitivity in men who are overweight/obese. Future studies are needed to investigate further whether oxygen signaling is a promising target to mitigate metabolic complications in obesity. CLINICAL TRIAL REGISTRATION This study is registered at the Netherlands Trial Register (NL7120/NTR7325).
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The Impact of Vegan and Vegetarian Diets on Physical Performance and Molecular Signaling in Skeletal Muscle.
Pohl, A, Schünemann, F, Bersiner, K, Gehlert, S
Nutrients. 2021;(11)
Abstract
Muscular adaptations can be triggered by exercise and diet. As vegan and vegetarian diets differ in nutrient composition compared to an omnivorous diet, a change in dietary regimen might alter physiological responses to physical exercise and influence physical performance. Mitochondria abundance, muscle capillary density, hemoglobin concentration, endothelial function, functional heart morphology and availability of carbohydrates affect endurance performance and can be influenced by diet. Based on these factors, a vegan and vegetarian diet possesses potentially advantageous properties for endurance performance. Properties of the contractile elements, muscle protein synthesis, the neuromuscular system and phosphagen availability affect strength performance and can also be influenced by diet. However, a vegan and vegetarian diet possesses potentially disadvantageous properties for strength performance. Current research has failed to demonstrate consistent differences of performance between diets but a trend towards improved performance after vegetarian and vegan diets for both endurance and strength exercise has been shown. Importantly, diet alters molecular signaling via leucine, creatine, DHA and EPA that directly modulates skeletal muscle adaptation. By changing the gut microbiome, diet can modulate signaling through the production of SFCA.