Next steps to advance general physical activity recommendations towards physical exercise prescription: a narrative review.

Physical inactivity is a major health concern, associated with the development of several non-communicable diseases and with an increased mortality rate. Therefore, promoting active lifestyles has become a crucial public health necessity for enhancing overall health and quality of life. The WHO guidelines for physical activity (PA) present valuable contributions in this respect; however, we believe that greater specificity should be added or complemented towards physical exercise (PE) testing, prescription and programming in future recommendations. In this review article, we suggest simple and practical tools accessible to the entire population to improve the specificity of this approach, highlighting aspects of PE programming used by trained subjects. By adopting these suggestions, exercise professionals, clinicians and physical trainers can optimise the current general PA recommendations towards PE prescription to improve fitness status and encourage PE adherence in the general population.

Changes in Blood Markers of Oxidative Stress, Inflammation and Cardiometabolic Patients with COPD after Eccentric and Concentric Cycling Training.

Chronic obstructive pulmonary disease (COPD) patients manifest muscle dysfunction and impaired muscle oxidative capacity, which result in reduced exercise capacity and poor health status. This study examined the effects of 12-week eccentric (ECC) and concentric (CONC) cycling training on plasma markers of cardiometabolic health, oxidative stress, and inflammation in COPD patients. A randomized trial in which moderate COPD was allocated to ECC (n = 10; 68.2 ± 10.0 year) or CONC (n = 10; 71.1 ± 10.3 year) training groups. Participants performed 12-week ECC or CONC training, 2-3 sessions per week, 10 to 30 min per session. Before and after training, peak oxygen consumption, maximal power output (VO2peak and POmax), and time-to-exhaustion (TTE) tests were performed. Plasma antioxidant and oxidative markers, insulin resistance, lipid profile, and systemic inflammation markers were measured before and after training at rest. VO2peak, POmax and TTE remained unchanged after ECC and CONC. CONC induced an increase in antioxidants (p = 0.01), while ECC decreased antioxidant (p = 0.02) markers measured at rest. CONC induced lesser increase in oxidative stress following TTE (p = 0.04), and a decrease in insulin resistance (p = 0.0006) compared to baseline. These results suggest that CONC training induced an increase in insulin sensitivity, antioxidant capacity at rest, and lesser exercise-induced oxidative stress in patients with moderate COPD.

Role of specialized pro-resolving mediators on inflammation, cardiometabolic health, disease progression, and quality of life after omega-3 PUFA supplementation and aerobic exercise training in individuals with rheumatoid arthritis: a randomized 16-week, placebo-controlled interventional trial.

Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by autoantibody production and synovial membrane damage. It significantly impairs overall function and quality of life. Consumption of omega-3 (n-3) polyunsaturated fatty acids (PUFAs) and regular aerobic exercise (AEx) training are reported to have positive effects on the progression of RA. However, the mechanisms behind these benefits are still inconclusive. This study protocol will investigate the effects of n-3 PUFA supplementation and AEx training on disease progression, cardiometabolic health, and quality of life, and their association with the plasma and synovial fluid levels of specialized pro-resolving mediators (SPMs) in subjects with RA. Methods: The study consists of a 16-week intervention period, during which participants will be randomly assigned in a double-blinded manner to one of four groups: placebo control (PLA), PLA+AEx, n-3, or n-3+AEx. The PLA groups will be given a gelatin-filled capsule, while the n-3 groups will be given n-3 PUFAs equivalent to 2.5 g/d of docosahexaenoic acid and 0.5 g/d of eicosapentaenoic acid. The AEx groups will perform exercise three times per week on a stationary electronically braked cycle ergometer at 60-70% of their VO2peak for 50-60 minutes. Before and after the intervention, participants will undergo RA-specific and functional measurements, peak aerobic capacity test, and a dietary and physical activity assessment. Venous blood and synovial fluid from the knee joint will be collected. Changes in disease progression, cardiometabolic health, and quality of life, as well as erythrocyte membrane composition to assess n-3 incorporation, SPM levels, inflammatory markers, and gene expression from blood and synovial fluid will be analyzed. Conclusions: The study aims to elucidate the SPMs that regulate the inflammatory gene expression pathways and associate them with the improvements in disease progression, cardiometabolic health, and quality of life after n-3 PUFA supplementation and AEx training. Registration: ClinicalTrials.gov #NCT05945693.

Community strategies for health promotion and prevention of chronic non-communicable diseases with a focus on physical activity and nutrition: the URO/FOCOS study protocol.

Non-communicable diseases (NCDs) account for 71% of all annual deaths, totaling 41 million people worldwide. The development and progression of these diseases are highly related to the environment and lifestyle choices, among which physical inactivity and excess malnutrition stand out. Currently, in Chile, there is no evidence at the regional and local level on the impact of physical activity and healthy nutrition plans and interventions on health promotion, prevention, and timely treatment of NCDs. The following protocol delineates the URO/FOCOS (Universidad Regional de O'Higgins/FOrtaleciendo COmunidades Saludables- Regional University of O'Higgins/Strengthening Healthy Communities) study, which will assess pilot community intervention strategies using a participatory action research approach by identifying barriers and facilitators on the practice of physical activity and healthy eating habits. In this project, the community from the O'Higgins region will be involved throughout the entire research process to develop strategies that promote regular physical activity and healthy eating practices. We propose three interrelated strategies: (1) Participatory Action Research, (2) Community interventions for promoting physical activity and healthy nutrition practices, and (3) health education. The URO/FOCOS study offers a unique opportunity in the O'Higgins region to develop participatory strategies and interventions based on the community's needs and motivations with regard to physical activity and healthy eating habits. We believe these strategies will help to improve the community's overall health through effective changes in their decision and preferences toward a more active lifestyle and healthier nutrition practices.

Effects of eccentric, concentric and eccentric/concentric training on muscle function and mass, functional performance, cardiometabolic health, quality of life and molecular adaptations of skeletal muscle in COPD patients: a multicentre randomised trial.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is the third cause of death worldwide. COPD is characterised by dyspnoea, limited exercise tolerance, and muscle dysfunction. Muscle dysfunction has been linked to dysregulation between muscle protein synthesis, myogenesis and degradation mechanisms. Conventional concentric cycling has been shown to improve several clinical outcomes and reduce muscle wasting in COPD patients. Eccentric cycling is a less explored exercise modality that allows higher training workloads imposing lower cardio-metabolic demand during exercise, which has shown to induce greater muscle mass and strength gains after training. Interestingly, the combination of eccentric and concentric cycling training has scarcely been explored. The molecular adaptations of skeletal muscle after exercise interventions in COPD have shown equivocal results. The mechanisms of muscle wasting in COPD and whether it can be reversed by exercise training are unclear. Therefore, this study aims two-fold: (1) to compare the effects of 12 weeks of eccentric (ECC), concentric (CONC), and combined eccentric/concentric (ECC/CONC) cycling training on muscle mass and function, cardiometabolic health, physical activity levels and quality of life in severe COPD patients; and (2) to examine the molecular adaptations regulating muscle growth after training, and whether they occur similarly in specific muscle fibres (i.e., I, IIa and IIx). METHODS: Study 1 will compare the effects of 12 weeks of CONC, ECC, versus ECC/CONC training on muscle mass and function, cardiometabolic health, levels of physical activity and quality of life of severe COPD patients using a multicentre randomised trial. Study 2 will investigate the effects of these training modalities on the molecular adaptations regulating muscle protein synthesis, myogenesis and muscle degradation in a subgroup of patients from Study 1. Changes in muscle fibres morphology, protein content, genes, and microRNA expression involved in skeletal muscle growth will be analysed in specific fibre-type pools. DISCUSSION: We aim to demonstrate that a combination of eccentric and concentric exercise could maximise the improvements in clinical outcomes and may be ideal for COPD patients. We also expect to unravel the molecular mechanisms underpinning muscle mass regulation after training in severe COPD patients. TRIAL REGISTRY: Deutshches Register Klinischer Studien; Trial registration: DRKS00027331; Date of registration: 12 January 2022. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00027331 .

NLRP3 Inflammasome: Potential Role in Obesity Related Low-Grade Inflammation and Insulin Resistance in Skeletal Muscle.

Among multiple mechanisms, low-grade inflammation is critical for the development of insulin resistance as a feature of type 2 diabetes. The nucleotide-binding oligomerization domain-like receptor family (NOD-like) pyrin domain containing 3 (NLRP3) inflammasome has been linked to the development of insulin resistance in various tissues; however, its role in the development of insulin resistance in the skeletal muscle has not been explored in depth. Currently, there is limited evidence that supports the pathological role of NLRP3 inflammasome activation in glucose handling in the skeletal muscle of obese individuals. Here, we have centered our focus on insulin signaling in skeletal muscle, which is the main site of postprandial glucose disposal in humans. We discuss the current evidence showing that the NLRP3 inflammasome disturbs glucose homeostasis. We also review how NLRP3-associated interleukin and its gasdermin D-mediated efflux could affect insulin-dependent intracellular pathways. Finally, we address pharmacological NLRP3 inhibitors that may have a therapeutical use in obesity-related metabolic alterations.

Changes in pulmonary and plasma oxidative stress and inflammation following eccentric and concentric cycling in stable COPD patients.

PURPOSE: The purpose of this study was to compare pulmonary and plasma markers of oxidative stress and inflammation after concentric and eccentric cycling bouts in individuals with chronic obstructive pulmonary disease (COPD). METHODS: Ten patients with moderate COPD level (68.3 ± 9.1 years; forced expiratory volume in 1 s = 68.6 ± 20.4% of predicted) performed 30 min of moderate-intensity concentric (CONC-M: 50% maximum concentric cycling power output; POmax) and eccentric cycling (ECC-M: 50% POmax), and high-intensity eccentric cycling (ECC-H: 100% POmax) in a randomised order. Cardiometabolic demand was monitored during cycling. Indirect markers of muscle damage were assessed before, immediately after, 24 and 48 h after cycling (muscle strength, muscle soreness and creatine kinase activity). Plasma oxidative stress (malondialdehyde: MDA), antioxidant (glutathione peroxidase activity: GPx) and inflammatory markers (IL-6, TNF-α) were measured before and 5 min after cycling. Exhaled breath condensate (EBC) samples were collected before and 15 min after cycling and analysed for hydrogen peroxide (H2O2), nitrites (NO2-) and pH. RESULTS: Cardiometabolic demand was 40-50% lesser for ECC-M than CONC-M and ECC-H. Greater muscle damage was induced after ECC-H than ECC-M and CONC-M. MDA decreased immediately after CONC-M (- 28%), ECC-M (- 14%), and ECC-H (- 17%), while GPx remained unchanged. IL-6 increased only after ECC-H (28%), while TNF-α remained unchanged after exercise. Pulmonary H2O2, NO2- and pH remained unchanged after exercise. CONCLUSION: These results suggest that only moderate muscle damage and inflammation were induced after high-intensity eccentric cycling, which did not induce pulmonary or plasmatic increases in markers of oxidative stress. TRIAL REGISTRATION NUMBER: Trial registration number: DRKS00009755.

High extracellular ATP levels released through pannexin-1 channels mediate inflammation and insulin resistance in skeletal muscle fibres of diet-induced obese mice.

AIMS/HYPOTHESIS: Skeletal muscle is a key target organ for insulin's actions and is the main regulator of blood glucose. In obese individuals and animal models, there is a chronic low-grade inflammatory state affecting highly metabolic organs, leading to insulin resistance. We have described that adult skeletal muscle fibres can release ATP to the extracellular medium through pannexin-1 (PANX1) channels. Besides, it is known that high extracellular ATP concentrations can act as an inflammatory signal. Here, we propose that skeletal muscle fibres from obese mice release high levels of ATP, through PANX1 channels, promoting inflammation and insulin resistance in muscle cells. METHODS: C57BL/6J mice were fed with normal control diet (NCD) or high-fat diet (HFD) for 8 weeks. Muscle fibres were isolated from flexor digitorum brevis (FDB) muscle. PANX1-knockdown FDB fibres were obtained by in vivo electroporation of a short hairpin RNA Panx1 plasmid. We analysed extracellular ATP levels in a luciferin/luciferase assay. Gene expression was studied with quantitative real-time PCR (qPCR). Protein levels were evaluated by immunoblots, ELISA and immunofluorescence. Insulin sensitivity was analysed in a 2-NBDG (fluorescent glucose analogue) uptake assay, immunoblots and IPGTT. RESULTS: HFD-fed mice showed significant weight gain and insulin resistance compared with NCD-fed mice. IL-6, IL-1ß and TNF-α protein levels were increased in FDB muscle from obese mice. We observed high levels of extracellular ATP in muscle fibres from obese mice (197 ± 55 pmol ATP/µg RNA) compared with controls (32 ± 10 pmol ATP/µg RNA). ATP release in obese mice fibres was reduced by application of 100 µmol/l oleamide (OLE) and 5 µmol/l carbenoxolone (CBX), both PANX1 blockers. mRNA levels of genes linked to inflammation were reduced using OLE, CBX or 2 U/ml ATPase apyrase in muscle fibres from HFD-fed mice. In fibres from mice with pannexin-1 knockdown, we observed diminished extracellular ATP levels (78 ± 10 pmol ATP/µg RNA vs 252 ± 37 pmol ATP/µg RNA in control mice) and a lower expression of inflammatory markers. Moreover, a single pulse of 300 µmol/l ATP to fibres from control mice reduced insulin-mediated 2-NBDG uptake and promoted an elevation in mRNA levels of inflammatory markers. PANX-1 protein levels were increased two- to threefold in skeletal muscle from obese mice compared with control mice. Incubation with CBX increased Akt activation and 2-NBDG uptake in HFD fibres after insulin stimulation, rescuing the insulin resistance condition. Finally, in vivo treatment of HFD-fed mice with CBX (i.p. injection of 10 mg/kg each day) for 14 days, compared with PBS, reduced extracellular ATP levels in skeletal muscle fibres (51 ± 10 pmol ATP/µg RNA vs 222 ± 28 pmol ATP/µg RNA in PBS-treated mice), diminished inflammation and improved glycaemic management. CONCLUSIONS/INTERPRETATION: In this work, we propose a novel mechanism for the development of inflammation and insulin resistance in the skeletal muscle of obese mice. We found that high extracellular ATP levels, released by overexpressed PANX1 channels, lead to an inflammatory state and insulin resistance in skeletal muscle fibres of obese mice.

Moderate Exercise in Spontaneously Hypertensive Rats Is Unable to Activate the Expression of Genes Linked to Mitochondrial Dynamics and Biogenesis in Cardiomyocytes.

Hypertension (HTN) is a public health concern and a major preventable cause of cardiovascular disease (CVD). When uncontrolled, HTN may lead to adverse cardiac remodeling, left ventricular hypertrophy, and ultimately, heart failure. Regular aerobic exercise training exhibits blood pressure protective effects, improves myocardial function, and may reverse pathologic cardiac hypertrophy. These beneficial effects depend at least partially on improved mitochondrial function, decreased oxidative stress, endothelial dysfunction, and apoptotic cell death, which supports the general recommendation of moderate exercise in CVD patients. However, most of these mechanisms have been described on healthy individuals; the effect of moderate exercise on HTN subjects at a cellular level remain largely unknown. We hypothesized that hypertension in adult spontaneously hypertensive rats (SHRs) reduces the mitochondrial response to moderate exercise in the myocardium. Methods: Eight-month-old SHRs and their normotensive control-Wistar-Kyoto rats (WKYR)-were randomly assigned to moderate exercise on a treadmill five times per week with a running speed set at 10 m/min and 15° inclination. The duration of each session was 45 min with a relative intensity of 70-85% of the maximum O2 consumption for a total of 8 weeks. A control group of untrained animals was maintained in their cages with short sessions of 10 min at 10 m/min two times per week to maintain them accustomed to the treadmill. After completing the exercise protocol, we assessed maximum exercise capacity and echocardiographic parameters. Animals were euthanized, and heart and muscle tissue were harvested for protein determinations and gene expression analysis. Measurements were compared using a nonparametric ANOVA (Kruskal-Wallis), with post-hoc Dunn's test. Results: At baseline, SHR presented myocardial remodeling evidenced by left ventricular hypertrophy (interventricular septum 2.08 ± 0.07 vs. 1.62 ± 0.08 mm, p < 0.001), enlarged left atria (0.62 ± 0.1 mm vs. 0.52 ± 0.1, p = 0.04), and impaired diastolic function (E/A ratio 2.43 ± 0.1 vs. 1.56 ± 0.2) when compared to WKYR. Moderate exercise did not induce changes in ventricular remodeling but improved diastolic filling pattern (E/A ratio 2.43 ± 0.1 in untrained SHR vs. 1.89 ± 0.16 trained SHR, p < 0.01). Histological analysis revealed increased myocyte transversal section area, increased Myh7 (myosin heavy chain 7) expression, and collagen fiber accumulation in SHR-control hearts. While the exercise protocol did not modify cardiac size, there was a significant reduction of cardiomyocyte size in the SHR-exercise group. Conversely, titin expression increased only WYK-exercise animals but remained unchanged in the SHR-exercise group. Mitochondrial response to exercise also diverged between SHR and WYKR: while moderate exercise showed an apparent increase in mRNA levels of Ppargc1α, Opa1, Mfn2, Mff, and Drp1 in WYKR, mitochondrial dynamics proteins remained unchanged in response to exercise in SHR. This finding was further confirmed by decreased levels of MFN2 and OPA1 in SHR at baseline and increased OPA1 processing in response to exercise in heart. In summary, aerobic exercise improves diastolic parameters in SHR but fails to activate the cardiomyocyte mitochondrial adaptive response observed in healthy individuals. This finding may explain the discrepancies on the effect of exercise in clinical settings and evidence of the need to further refine our understanding of the molecular response to physical activity in HTN subjects.

Defective fasting-induced PKA activation impairs adipose tissue glycogen degradation in obese Zucker rats.

BACKGROUND: Obesity is associated with development of insulin resistance in adipose tissue (AT). Human obesity has been associated with increased glycogen deposition in adipocytes. Adipocytes synthesise glycogen prior to the formation of lipids. The present study examined adipose glycogen content in obese Zucker rats and the effect of fasting on glycogen-metabolising enzymes. We hypothesised that obesity imposes a blunted response to fasting through impaired activation of glycogen-metabolizing enzymes, which dampens glycogen mobilization in obese Zucker rats. METHODS: We investigated the effect of 24h fasting on AT glycogen metabolism in 12-week old obese Zucker rats. Epididymal fat pads were collected from rats fed ad-libitum and fasted for 24h. Glycogen content, glycogen synthase and phosphorylase enzyme activity, and PKA activity were analysed as well as total and phosphorylated protein content for glycogen-metabolizing enzymes glycogen synthase and phosphorylase, glucose transporter GLUT4, and cAMP-dependent response element binding protein levels. RESULTS: Twelve-week old obese Zucker rats showed increased AT glycogen content (adipose glycogen content [mean ± SD], lean: 3.95 ± 2.78 to 0.75 + 0.69 µg.mg-1; p < 0.005 fed vs fasted, and obese: 5.23 ± 3.38 to 5.019 ± 1.99 µg.mg-1; p = ns fed and fasted and p < 0.005 lean vs obese), and impaired fasting-induced glycogen mobilization following a 24h fast. These defects were associated with dysfunctional glycogen-metabolizing enzymes, characterized by: (1) blunted phosphorylation-mediated activation and downregulated protein expression of glycogen phosphorylase, and (2) an impaired phosphorylation-mediated inactivation of glycogen synthase. Furthermore, these defects were related to impaired fasting-induced protein kinase A (PKA) activation. CONCLUSION: This study provides evidence of a defective glycogen metabolism in the adipose associated with impaired fasting-induced activation of the upstream kinase protein kinase A, which render a converging point to obesity-related primary alterations in carbohydrate and lipid metabolism in the AT.

Activation of protein synthesis, regeneration, and MAPK signaling pathways following repeated bouts of eccentric cycling.

The aim of this study was to examine the activation of skeletal muscle signaling pathways related to protein synthesis and the gene expression of regeneration/degradation markers following repeated bouts of eccentric cycling. Nine untrained men (25.4 ± 1.9 yr) performed two 30-min eccentric cycling bouts (ECC1, ECC2) at 85% of maximal concentric workload, separated by 2 wk. Muscle biopsies were taken from the vastus lateralis before and 2 h after each bout. Indirect markers of muscle damage were assessed before and 24-48 h after exercise. Changes in the Akt/mammalian target of rapamycin (mTOR)/rbosomal protein S6 kinase 1 (S6K1)/ribosomal protein S6 (rpS6) and MAPK signaling pathways were measured by Western blot and changes in mRNA expression of IL-6 and IL-1ß, and myogenic regulatory factors (MRFs) were measured by real-time PCR. ECC1 induced greater increases in indirect markers of muscle damage compared with ECC2. Phosphorylation of S6K1 and rpS6 increased after both exercise bouts (P < 0.05), whereas phosphorylation of mTOR increased after ECC2 only (P = 0.03). Atrogin-1 mRNA expression decreased after ECC1 and ECC2 (P < 0.05) without changes in muscle RING-finger protein-1 mRNA. Basal mRNA levels of myoblast determination protein-1 (MyoD), MRF4, and myogenin were higher 2 wk after ECC1 (P < 0.05). MRF4 mRNA increased after ECC1 and ECC2 (P < 0.05), whereas MyoD mRNA expression increased only after ECC1 (P = 0.03). Phosphorylation of JNK and p38 MAPK increased after both exercise bouts (P < 0.05), similar to IL-6 and IL-1ß mRNA expression. All together, these results suggest that differential regulation of the mTOR pathway and MRF expression could mediate the repeated bout effect observed between an initial and secondary bout of eccentric exercise.