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Mammalian skeletal muscles contain varying proportions of Type I and II fibers, which feature different structural, metabolic and functional properties. According to these properties, skeletal muscles are labeled as ‘red’ or ‘white’, ‘oxidative’ or ‘glycolytic’, ‘slow-twitch’ or ‘fast-twitch’, respectively. Redox processes (i.e., redox signaling and oxidative stress) are increasingly recognized as a fundamental part of skeletal muscle metabolism at rest, during and after exercise. The aim of the present review was to investigate the potential redox differences between slow- (composed mainly of Type I fibers) and fast-twitch (composed mainly of Type IIa and IIb fibers) muscles at rest and after a training protocol. Slow-twitch muscles were almost exclusively represented in the literature by the soleus muscle, whereas a wide variety of fast-twitch muscles were used. Based on our analysis, we argue that slow-twitch muscles exhibit higher antioxidant enzyme activity compared to fast-twitch muscles in both pre- and post-exercise training. This is also the case between heads or regions of fast-twitch muscles that belong to different subcategories, namely Type IIa (oxidative) versus Type IIb (glycolytic), in favor of the former. No safe conclusion could be drawn regarding the mRNA levels of antioxidant enzymes either pre- or post-training. Moreover, slow-twitch skeletal muscles presented higher glutathione and thiol content as well as higher lipid peroxidation levels compared to fast-twitch. Finally, mitochondrial hydrogen peroxide production was higher in fast-twitch muscles compared to slow-twitch muscles at rest. This redox heterogeneity between different muscle types may have ramifications in the analysis of muscle function and health and should be taken into account when designing exercise studies using specific muscle groups (e.g., on an isokinetic dynamometer) or isolated muscle fibers (e.g., electrical stimulation) and may deliver a plausible explanation for the conflicting results about the ergogenic potential of antioxidant supplements.

Formidable and often seemingly insurmountable conceptual, technical, and methodological challenges hamper the measurement of oxidative stress in humans. For instance, fraught and flawed methods, such as the thiobarbituric acid reactive substances assay kits for lipid peroxidation, rate-limit progress. To advance translational redox research, we present ten comprehensive “cheat codes” for measuring oxidative stress in humans. The cheat codes include analytical approaches to assess reactive oxygen species, antioxidants, oxidative damage, and redox regulation. They provide essential conceptual, technical, and methodological information inclusive of curated “do” and “don’t” guidelines. Given the biochemical complexity of oxidative stress, we present a research question-grounded decision tree guide for selecting the most appropriate cheat code(s) to implement in a prospective human experiment. Worked examples demonstrate the benefits of the decision tree-based cheat code selection tool. The ten cheat codes define an invaluable resource for measuring oxidative stress in humans.

At the dawn of the 20th century, seminal studies revealed that muscle fibers produce less heat and generate greater force during elongation than during shortening actions, laying the foundation for contemporary research on eccentric exercise. Today, eccentric exercise is widely used by athletes to enhance strength and by older adults to maintain functional capacity, yet it may cause muscle damage, particularly in unaccustomed muscles. Despite more than a century of investigation, the precise mechanisms of eccentric exercise-induced muscle damage remain incompletely resolved. Nevertheless, eccentric exercise serves as a valuable model for studying muscle injury and repair and adaptation. This review organizes current evidence into nine key themes: (1) eccentric exercise-induced muscle damage and flawed biomarkers, (2) satellite cell-mediated and alternative repair pathways, (3) high-force, low-cost contractions and metabolic impact, (4) repeated bout effect and protective adaptations, (5) architectural remodeling of fascicles, sarcomeres and tendon, (6) distinct neural control, proprioception, and cross-education adaptations, (7) mitochondrial, sarcoplasmic reticulum, and cytoskeletal stress remodeling, (8) connective tissue perturbation, remodeling, and joint stability, and (9) targeted, cautious use of antioxidant supplementation. Rather than offering a comprehensive overview, this review highlights pivotal experiments, concepts, and controversies within these themes to guide readers to the most impactful discoveries in eccentric exercise and muscle damage.

The aim of the present study was to study the effects of cycling and pure concentric and pure eccentric high-intensity interval exercise (HIIE) on skeletal muscle (i.e., vastus lateralis) and cerebral oxygenation. Twelve healthy males (n = 12, age 26 ± 1 yr, body mass 78 ± 2 kg, height 176 ± 2 cm, body fat 17 ± 1% of body mass) performed, in a random order, cycling exercise and isokinetic concentric and eccentric exercise. The isokinetic exercises were performed on each randomly selected leg. The muscle and the cerebral oxygenation were assessed by measuring oxyhemoglobin, deoxyhemoglobin, total hemoglobin, and tissue saturation index. During the cycling exercise, participants performed seven sets of seven seconds maximal intensity using a load equal to 7.5% of their body mass while, during isokinetic concentric and eccentric exercise, they were performed seven sets of five maximal muscle contractions. In all conditions, a 15 s rest was adopted between sets. The cycling HIIE caused greater fatigue (i.e., greater decline in fatigue index) compared to pure concentric and pure eccentric isokinetic exercise. Muscle oxygenation was significantly reduced during HIIE in the three exercise modes, with no difference between them. Cerebral oxygenation was affected only marginally during cycling exercise, while no difference was observed between conditions. It is concluded that a greater volume of either concentric or eccentric isokinetic maximal intensity exercise is needed to cause exhaustion which, in turn, may cause greater alterations in skeletal muscle and cerebral oxygenation.

PurposeAcute high-intensity unaccustomed eccentric exercise performed by naive subjects is accompanied by disturbances in muscle damage biomarkers. The aim of the study was to investigate whether a causal relationship indeed exists between eccentric exercise and muscle damage.MethodsTwenty-four men randomly assigned into a concentric only or an eccentric-only training group and performed 10 weeks of isokinetic resistance exercise (one session/week of 75 maximal knee extensors actions). Physiological markers of muscle function and damage (i.e., range of motion, delayed onset muscle soreness, isometric, concentric and eccentric peak torque) were assessed prior to and 1–3 and 5 days post each session. Biochemical markers of muscle damage (creatine kinase) and inflammation (C-reactive protein) were measured prior and 2 days post each session.ResultsAfter the first bout, eccentric exercise induced greater muscle damage compared to concentric exercise; however, during the nine following sessions, this effect progressively diminished, while after the 10th week of training, no alterations in muscle damage biomarkers were observed after either exercise protocol. Additionally, strength gains at the end of the training period were comparable between the two groups and were mode-specific.Conclusion(1) eccentric exercise per se does not affect muscle damage biomarkers; (2) muscle damage occurs as a result of muscle unaccustomedness to this action type; (3) exercise-induced muscle damage is not a prerequisite for increased muscle strength. Collectively, we believe that muscle unaccustomedness to high-intensity eccentric exercise, and not eccentric exercise per se, is the trigger for muscle damage as indicated by muscle damage biomarkers.

There is a lack of consensus on optimal timing to assess redox biomarkers post‐exercise, limiting methodological standardisation and linking oxidative stress to physiology. We determined optimal post‐exercise oxidative stress assessment times using three redox biomarkers: glutathione, F 2 ‐isoprostanes and protein carbonyls. Standardised mean differences were calculated using random‐effects models, with 95% confidence and prediction intervals. Risk of bias was assessed via RoB2 and ROBINS‐I tools. Egger's test and funnel plots evaluated publication bias. Certainty of evidence was rated using GRADE. PROSPERO preregistration: CRD42024508049. A total of 103 studies ( n  = 1418) were included. Glutathione levels decreased immediately ( g  = −0.70; 95% CI: −0.96, −0.44; P  < 0.001), at 30 min to 2 h ( g  = −0.81; 95% CI: −1.19, −0.43; P  < 0.001), and 48 h post‐exercise ( g  = −0.98; 95% CI: −1.50, −0.46; P  < 0.01). F 2 ‐isoprostanes increased immediately post‐exercise ( g  = 1.01; 95% CI: 0.70, 1.33; P  < 0.001) and at 30 min to 2 h ( g  = 0.46; 95% CI: 0.23, 0.69; P  < 0.001). Protein carbonyls increased at all time points, especially at 48 h post‐exercise ( g  = 1.17; 95% CI: 0.73, 1.60; P  < 0.001), peaking at 72 h ( g  = 1.33; 95% CI: 0.52, 2.14; P  = 0.0048). Subgroup analyses revealed that non‐muscle‐damaging exercise elicits responses immediately after exercise or within the first 2 h, while muscle‐damaging exercise induces peaks at 48 and 72 h post‐exercise. Egger's test indicated publication bias for F 2 ‐isoprostanes ( P  = 0.017) and protein carbonyls ( P  = 0.031) post‐exercise. Risk of bias was moderate in randomised controlled trials and serious in non‐randomised studies. Certainty of evidence ranged from moderate to high. In conclusion, non‐muscle‐damaging exercise elicits early responses within hours, while muscle‐damaging protocols produce delayed peaks at 48–72 h. These findings support methodological consistency and are useful for optimising study design, sample size estimation and providing links between redox biology and physiological outcomes. What is the topic of this review? The optimal timing to assess exercise‐induced oxidative stress in humans, via a systematic review and meta‐analysis of three commonly used redox biomarkers: glutathione (antioxidant), F 2 ‐isoprostanes (lipid peroxidation product) and protein carbonyls (protein oxidation product). What advances does it highlight? It delineates biomarker‐ and protocol‐specific kinetics: non‐muscle‐damaging exercise peaks immediately/within 2 h, while muscle‐damaging protocols peak at 48–72 h. It offers specimen guidance, quantifies effect sizes, grades evidence and provides practical standards for study design.

The present study aimed to investigate whether acute L-citrulline supplementation would affect inspiratory muscle oxygenation and respiratory performance. Twelve healthy males received 6 g of L-citrulline or placebo in a double-blind crossover design. Pulmonary function (i.e., forced expired volume in 1 s, forced vital capacity and their ratio), maximal inspiratory pressure (MIP), fractional exhaled nitric oxide (NO•), and sternocleidomastoid muscle oxygenation were measured at baseline, one hour post supplementation, and after an incremental resistive breathing protocol to task failure of the respiratory muscles. The resistive breathing task consisted of 30 inspirations at 70% and 80% of MIP followed by continuous inspirations at 90% of MIP until task failure. Sternocleidomastoid muscle oxygenation was assessed using near-infrared spectroscopy. One-hour post-L-citrulline supplementation, exhaled NO• was significantly increased (19.2%; p < 0.05), and this increase was preserved until the end of the resistive breathing (16.4%; p < 0.05). In contrast, no difference was observed in the placebo condition. Pulmonary function and MIP were not affected by the L-citrulline supplementation. During resistive breathing, sternocleidomastoid muscle oxygenation was significantly reduced, with no difference noted between the two supplementation conditions. In conclusion, a single ingestion of 6 g L-citrulline increased NO• bioavailability but not the respiratory performance and inspiratory muscle oxygenation.

In sports nutrition, nitric oxide (NO•) precursors such as L-citrulline are widely used to enhance NO• bioavailability, which is considered an ergogenic aid. Our study aimed to examine the effect of short-term L-citrulline supplementation on respiratory muscles’ performance, fatigue, and oxygenation in older adults. Fourteen healthy older males took 6 g of L-citrulline or a placebo for seven days in a double-blind crossover design. Pulmonary function via spirometry (i.e., forced expired volume in 1 s (FEV1), forced vital capacity (FVC), and their ratio)), fractional exhaled nitric oxide (NO•), maximal inspiratory pressure (MIP), rate of perceived exertion, and sternocleidomastoid muscle oxygenation (i.e., oxyhemoglobin (Δ[O2Hb]) and de-oxyhemoglobin (Δ[HHb]), total hemoglobin concentration (Δ[tHb]), and tissue saturation index (TSI%)) were evaluated at baseline, after seven days of L-citrulline supplementation, and after incremental resistive breathing to task failure of the respiratory muscles. The exhaled NO• value was only significantly increased after the supplementation (26% p < 0.001) in the L-citrulline condition. Pulmonary function, MIP, rate of perceived exertion, and sternocleidomastoid muscle oxygenation were not affected by the L-citrulline supplementation. In the present study, although short-term L-citrulline supplementation increased exhaled NO•, no ergogenic aids were found on the examined parameters at rest and after resistive breathing to task failure in older adults.

Since cysteine redox proteoforms (i) are virtually unstudied, we derived novel insights by computationally analysing the human proteome. Our analysis revealed a vast, effectively infinite, theoretical i space housing 3.02 x 10169 unique cysteine redox proteoforms. For >80% and 99% of the human proteome, the i space comprises 6.83 x 108 and 1.76 x 1031 unique proteoforms, respectively. The heterogenous distribution of the i space by gene ontology terms, suggests, but does not prove, functional speciation. To theoretically limit the number of cysteine redox proteoforms that can be “downloaded” from the abstract i “cloud”, we implement novel equations. Protein copy numbers limit the i space by 161-logs to 4.04 x 107 unique cysteine redox proteoforms per HeLa cell. An immutable law: the number of cysteine redox proteoform molecules (Ni) must equal the number of cysteine-containing protein molecules. We compute an Ni value of 1.70 x 109 per HeLa cell. While Ni will be displaced from thermodynamic equilibrium towards the reduced state (e.g., ≈90%-reduced), it is possible that the number of partially oxidised cysteine redox proteoform molecules is in the order of 106-8 per HeLa cell. Consistent with this, 100%-oxidised forms were observed in 60% of the proteins studied to date. Our analysis advances understanding of redox biology at the proteoform level.

This randomized controlled trial examined body mass, body composition, energy balance and performance responses of previously sedentary overweight/obese women to a circuit-type integrated neuromuscular training program with alternative modalities. Forty-nine healthy overweight or class I obese females (36.4±4.4 yrs) were randomly assigned to either a control (N = 21), training (N = 14) or training-detraining (N = 14) group. In weeks 1-20, the training groups trained three times/week using 10-12 whole-body exercises of progressively increased intensity/volume, organized in timed interval circuit form. In weeks 21-40, the training group continued training whereas the training-detraining group not. Heart rate, perceived exertion, blood lactate, exertion, oxygen consumption and excess post-exercise oxygen consumption were measured for one session/phase/person and exercise energy expenditure was calculated. Energy intake, habitual physical activity, resting metabolic rate, body composition, body mass, strength and maximal oxygen consumption were measured at baseline, mid-intervention and post-intervention. A two-way repeated measures ANOVA was used to determine differences between three time points and three groups. In C, VO2max declined (p<0.013) and body fat (p<0.008), waist (p<0.059) and hip (p<0.012) circumferences increased after 40 weeks compared to baseline. Training reduced body mass (6%, p<0.001), body fat (~5.5%, p<0.001) and increased fat-free mass (1.2-3.4%, p<0.05), strength (27.2%, p<0.001) and endurance (26.8%, p<0.001) after a 10-month implementation period using a metabolic overload of only 5-12 metabolic equivalents of task-hours per week. Training induced a long-term negative energy balance during an exercise and a non-exercise day due to an elevation of resting metabolic rate (6%-10%, p<0.05) and exercise-related energy expenditure. Training had an 8% and 94% attrition and attendance rates, respectively. Training-induced gains were attenuated but not lost following a 5-month detraining. A 10-month implementation of a high-intensity interval type training program elicited both endurance and musculoskeletal gains and resulted in a long-term negative energy balance that induced a progressive and sustained reduction of body and fat mass. ClinicalTrials.gov NCT03134781.