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Introduction: This study investigated the magnitude and etiology of neuromuscular fatigue and muscle damage induced by eccentric cycling compared with conventional concentric cycling in patients with breast cancer., Methods: After a gradual familiarization protocol for eccentric cycling, nine patients with early-stage breast cancer performed three cycling sessions in eccentric or concentric mode. The eccentric cycling session (ECC) was compared with concentric cycling sessions matched for power output (CON power ; 80% of concentric peak power output, 95 ± 23 W) or oxygen uptake ( ; 10 ± 2 mL·min·kg -1 ). Preexercise to postexercise changes (30-s through 10-min recovery) in knee extensor maximal voluntary contraction force (MVC), voluntary activation, and quadriceps potentiated twitch force ( Qtw ) were quantified to determine global, central, and peripheral fatigue, respectively. Creatine kinase and lactate dehydrogenase activities were measured in the plasma before and 24 h after exercise as markers of muscle damage., Results: Compared with CON power (-11% ± 9%) and (-5% ± 5%), the ECC session resulted in a greater decrease in MVC (-25% ± 12%) postexercise ( P < 0.001). Voluntary activation decreased only in ECC (-9% ± 6% postexercise, P < 0.001). The decrease in Qtw was similar postexercise between ECC and CON power (-39% ± 21% and -40% ± 16%, P > 0.99) but lower in ( P < 0.001). The CON power session resulted in twofold greater compared with the ECC and sessions ( P < 0.001). No change in creatine kinase or lactate dehydrogenase activity was reported from preexercise to 24 h postexercise., Conclusions: The ECC session induced greater neuromuscular fatigue compared with the concentric cycling sessions without generating severe muscle damage. ECC is a promising exercise modality for counteracting neuromuscular maladaptation in patients with breast cancer., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Sports Medicine.)

Objective: Existing literature indicates that females generally demonstrate higher fatigue resistance than males during isometric contractions. However, when it comes to single-limb dynamic exercises, the intricate interplay between performance fatigability (PF), cardiovascular responses, and muscle metabolism in relation to sex differences remains underexplored., Purpose: This study investigates how sex affects the relationship between muscle oxidative characteristics and the development of PF during dynamic single-leg exercise., Methods: Twenty-four young healthy participants (12 males vs. 12 females) performed a constant-load single-leg knee extension task (85% peak power output; 60 rpm) to exhaustion (TTE). Neuromuscular assessments via transcranial magnetic and peripheral stimulations were conducted pre- and post-exercise to evaluate central and peripheral factors of PF. Vastus lateralis muscle biopsies were obtained for mitochondrial respiration and immunohistochemistry analyses., Results: Participants performed similar total work (28 ± 7 vs. 27 ± 14 kJ, p = 0.81) and TTE (371 ± 139 vs. 377 ± 158 sec, p = 0.98); after the TTE, females' maximal isometric voluntary contraction (MVIC: -36 ± 13 vs. -24 ± 9 %, p = 0.006) and resting twitch (RT: (-65 ± 9 vs. -40 ± 24 %, p = 0.004) force declined less. No differences were observed in supraspinal neuromuscular factors (p > 0.05). During exercise, the cardiovascular responses differed between sexes. Although fiber type composition was similar (type I: 47 ± 13 vs. 56 ± 14 %, p = 0.11), males had lower mitochondrial net oxidative capacity (61 ± 30 vs. 89 ± 37, p = 0.049) and higher Complex II contribution to maximal respiration (CII; 59 ± 8 vs. 48 ± 6%, p < 0.001), which correlated with the decline in MVIC (r = -0.74, p < 0.001) and RT (r = -0.60, p = 0.002)., Conclusions: Females display greater resistance to PF during dynamic contractions, likely due to their superior mitochondrial efficiency and lower dependence on mitochondrial CII activity., Competing Interests: Conflict of Interest and Funding Source: This research was funded by the Italian Ministry of Research and University (MIUR; Rome, Italy) 5-year special funding (https://www.miur.gov.it/dipartimenti-di-eccellenza) and the research grant “Fondo Gianesini Emma” in collaboration with UniCredit Foundation and University of Verona (Italy). The authors declare no competing interest., (Copyright © 2024 by the American College of Sports Medicine.)

The force drop after transcranial magnetic stimulation (TMS) delivered to the motor cortex during voluntary muscle contractions could inform about muscle relaxation properties. Because of the physiological relation between skeletal muscle fiber-type distribution and size and muscle relaxation, TMS could be a noninvasive index of muscle relaxation in humans. By combining a noninvasive technique to record muscle relaxation in vivo (TMS) with the gold standard technique for muscle tissue sampling (muscle biopsy), we investigated the relation between TMS-induced muscle relaxation in unfatigued and fatigued states, and muscle fiber-type distribution and size. Sixteen participants (7F/9M) volunteered to participate. Maximal knee-extensor voluntary isometric contractions were performed with TMS before and after a 2-min sustained maximal voluntary isometric contraction. Vastus lateralis muscle tissue was obtained separately from the participants' dominant limb. Fiber type I distribution and relative cross-sectional area of fiber type I correlated with TMS-induced muscle relaxation at baseline ( r = 0.67, adjusted P = 0.01; r = 0.74, adjusted P = 0.004, respectively) and normalized TMS-induced muscle relaxation as a percentage of baseline ( r = 0.50, adjusted P = 0.049; r = 0.56, adjusted P = 0.031, respectively). The variance in the normalized peak relaxation rate at baseline (59.8%, P < 0.001) and in the fatigue resistance (23.0%, P = 0.035) were explained by the relative cross-sectional area of fiber type I to total fiber area. Fiber type I proportional area influences TMS-induced muscle relaxation, suggesting TMS as an alternative method to noninvasively inform about skeletal muscle relaxation properties. NEW & NOTEWORTHY Transcranial magnetic stimulation (TMS)-induced muscle relaxation reflects intrinsic muscle contractile properties by interrupting the drive from the central nervous system during voluntary muscle contractions. We showed that fiber type I proportional area influences the TMS-induced muscle relaxation, suggesting that TMS could be used for the noninvasive estimation of muscle relaxation in unfatigued and fatigued human muscles when the feasibility of more direct method to study relaxation properties (i.e., muscle biopsy) is restricted.

Aim: Force expression is characterized by an interplay of biological and molecular determinants that are expected to differentiate males and females in terms of maximal performance. These include muscle characteristics (muscle size, fiber type, contractility), neuromuscular regulation (central and peripheral factors of force expression), and individual genetic factors (miRNAs and gene/protein expression). This research aims to comprehensively assess these physiological variables and their role as determinants of maximal force difference between sexes., Methods: Experimental evaluations include neuromuscular components of isometric contraction, intrinsic muscle characteristics (proteins and fiber type), and some biomarkers associated with muscle function (circulating miRNAs and gut microbiome) in 12 young and healthy males and 12 females., Results: Male strength superiority appears to stem primarily from muscle size while muscle fiber-type distribution plays a crucial role in contractile properties. Moderate-to-strong pooled correlations between these muscle parameters were established with specific circulating miRNAs, as well as muscle and plasma proteins., Conclusion: Muscle size is crucial in explaining the differences in maximal voluntary isometric force generation between males and females with similar fiber type distribution. Potential physiological mechanisms are seen from associations between maximal force, skeletal muscle contractile properties, and biological markers., (© 2024 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

Previous studies in animal models showed that exercise-induced metabolites accumulation may sensitize the mechanoreflex-induced response. The aim of this study was to assess whether the magnitude of the central hemodynamic and ventilatory adjustments evoked by isolated stimulation of the mechanoreceptors in humans are influenced by the prior accumulation of metabolic byproducts in the muscle. 10 males and 10 females performed two exercise bouts consisting of 5-min of intermittent isometric knee-extensions performed 10% above the previously determined critical force. Post-exercise, the subjects recovered for 5 min either with a suprasystolic circulatory occlusion applied to the exercised quadriceps (PECO) or under freely-perfused conditions (CON). Afterwards, 1-min of continuous passive leg movement was performed. Central hemodynamics, pulmonary data, and electromyography from exercising/passively-moved leg were recorded throughout the trial. Root mean square of successive differences (RMSSD, index of vagal tone) was also calculated. Δpeak responses of heart rate (ΔHR) and ventilation ([Formula: see text]) to passive leg movement were higher in PECO compared to CON (ΔHR: 6 ± 5 vs 2 ± 4 bpm, p = 0.01; 3.9 ± 3.4 vs 1.9 ± 1.7 L min -1 , p = 0.02). Δpeak of mean arterial pressure (ΔMAP) was significantly different between conditions (5 ± 3 vs  - 3 ± 3 mmHg, p < 0.01). Changes in RMSSD with passive leg movement were different between PECO and CON (p < 0.01), with a decrease only in the former (39 ± 18 to 32 ± 15 ms, p = 0.04). No difference was found in all the other measured variables between conditions (p > 0.05). These findings suggest that mechanoreflex-mediated increases in HR and [Formula: see text] are sensitized by metabolites accumulation. These responses were not influenced by biological sex., (© 2023. The Author(s).)

Purpose: Both muscle mass and physical activity are independent mechanisms that play a role in vascular remodeling, however, the direct impact of muscle mass on the structure and function of the vessels is not clear. The aim of the study was to determine the impact of muscle mass alteration on lower limbs arterial diameter, blood flow, shear rate and arterial stiffness., Methods: Nine (33 ± 13 yrs) male individuals with a single-leg amputation were recruited. Vascular size (femoral artery diameter), hemodynamics (femoral artery blood flow and shear rate were measured at the level of the common femoral artery in both amputated (AL) and whole limbs (WL). Muscle mass of both limbs, including thigh for AL and thigh and leg for WL, was measured with a DXA system., Results: AL muscle mass was reduced compared to the WL (3.2 ± 1.2 kg vs. 9.4 ± 2.1 kg; p = 0.001). Diameter of the femoral artery was reduced in the AL (0.5 ± 0.1 cm) in comparison to the WL (0.9 ± 0.2 cm, p = 0.001). However, femoral artery blood flow normalized for the muscle mass (AL = 81.5 ± 78.7ml min -1  kg -1 ,WL = 32.4 ± 18.3; p = 0.11), and blood shear rate (AL = 709.9 ± 371.4 s -1 , WL = 526,9 ± 295,6; p = 0.374) were non different between limbs. A correlation was found only between muscle mass and femoral artery diameter (p = 0.003, R = 0.6561)., Conclusion: The results of this study revealed that the massive muscle mass reduction caused by a leg amputation, but independent from the level of physical activity, is coupled by a dramatic arterial diameter decrease. Interestingly, hemodynamics and arterial stiffness do not seem to be impacted by these structural changes., (© 2022. The Author(s).)

Background and Objective: Neuromuscular fatigue contributes to decrements in quality of life in Multiple Sclerosis (MS), yet available treatments demonstrate limited efficacy. Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique which presents promise in managing fatigue, possibly related to its capacity to modulate corticospinal excitability. There is evidence for capitalising on metaplasticity using tDCS for improving outcomes. However, this remains to be explored with fatigue in people with MS (pwMS). We investigated cathodal tDCS (ctDCS) priming on anodal tDCS (atDCS)-induced corticospinal excitability and fatigue modulation in pwMS., Methods: 15 pwMS and 15 healthy controls completed fatiguing exercise whilst receiving either ctDCS or sham (stDCS) primed atDCS to the motor cortex. We assessed change in contraction force and motor evoked potential (MEP) amplitude across time to represent changes in fatigue and corticospinal excitability., Results and Conclusion: ctDCS primed atDCS induced MEP elevation in healthy participants but not in pwMS, possibly indicating impaired metaplasticity in pwMS. No tDCS-mediated change in the magnitude of fatigue was observed, implying that development of fatigue may not rely on changes in corticospinal excitability., Significance: These findings expand understanding of tDCS effects in pwMS, highlighting differences that may be relevant in the disease pathophysiology., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2022. Published by Elsevier B.V.)

Purpose: This study evaluated whether central motor drive during fatiguing exercise plays a role in determining performance and the development of neuromuscular fatigue during a subsequent endurance task., Methods: On separate days, 10 males completed three constant-load (80% peak power output), single-leg knee-extension trials to task failure in a randomized fashion. One trial was performed without preexisting quadriceps fatigue (CON), and two trials were performed with preexisting quadriceps fatigue induced either by voluntary (VOL; involving central motor drive) or electrically evoked (EVO; without central motor drive) quadriceps contractions (~20% maximal voluntary contraction (MVC)). Neuromuscular fatigue was assessed via pre-post changes in MVC, voluntary activation (VA), and quadriceps potentiated twitch force ( Qtw,pot ). Cardiorespiratory responses and rating of perceived exertion were also collected throughout the sessions. The two prefatiguing protocols were matched for peripheral fatigue and stopped when Qtw,pot declined by ~35%., Results: Time to exhaustion was shorter in EVO (4.3 ± 1.3 min) and VOL (4.7 ± 1.5 min) compared with CON (10.8 ± 3.6 min, P < 0.01) with no difference between EVO and VOL. ΔMVC (EVO: -47% ± 8%, VOL: -45% ± 8%, CON: -53% ± 8%), Δ Qtw,pot (EVO: -65% ± 7%, VOL: -59% ± 14%, CON: -64% ± 9%), and ΔVA (EVO: -9% ± 7%, VOL: -8% ± 5%, CON: -7% ± 5%) at the end of the dynamic task were not different between conditions (all P > 0.05). Compared with EVO (10.6 ± 1.7) and CON (6.8 ± 0.8), rating of perceived exertion was higher ( P = 0.05) at the beginning of VOL (12.2 ± 1.0)., Conclusions: These results suggest that central motor drive involvement during prior exercise plays a negligible role on the subsequent endurance performance. Therefore, our findings indicate that peripheral fatigue-mediated impairments are the primary determinants of high-intensity single-leg endurance performance., (Copyright © 2022 by the American College of Sports Medicine.)

Transcranial magnetic stimulation (TMS)-induced relaxation rate reflects intrinsic muscle contractile properties by interrupting the drive from the central nervous system during voluntary muscle contractions. To determine the appropriateness of knee-extensor muscle relaxation measurements induced by TMS, this study aimed to establish both the within- and between-session reliability before and after a fatiguing exercise bout. Eighteen participants (9 females, 9 males, age 25 ± 2 years, height 171 ± 9 cm, body mass 68.5 ± 13.5 kg) volunteered to participate in two identical sessions approximately 30 days apart. Maximal and submaximal neuromuscular evaluations were performed with TMS six times before (PRE) and at the end (POST) of a 2-min sustained maximal voluntary isometric contraction. Within- and between-session reliability of PRE values were assessed with intraclass correlation coefficient (ICC 2,1 , relative reliability), repeatability coefficient (absolute reliability), and coefficient of variation (variability). Test-retest reliability of post-exercise muscle relaxation rates was assessed with Bland-Altman plots. For both the absolute and normalized peak relaxation rates and time to peak relaxation, data demonstrated low variability (e.g. coefficient of variation ≤ 7.8%) and high reliability (e.g. ICC 2,1  ≥ 0.963). Bland-Altman plots showed low systematic errors. These findings establish the reliability of TMS-induced muscle relaxation rates in unfatigued and fatigued knee-extensor muscles, showing that TMS is a useful technique that researchers can use when investigating changes in muscle relaxation rates both in unfatigued and fatigued knee-extensor muscles., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Fatigue is one of the most disabling symptoms of multiple sclerosis (MS); it influences patients' quality of life. The etiology of fatigue is complex, and its pathogenesis is still unclear and debated. The objective of this review was to describe potential brain structural and functional dysfunctions underlying fatigue symptoms in patients with MS. To reach this purpose, a systematic review was conducted of published studies comparing functional brain activation and structural brain in MS patients with and without fatigue. Electronic databases were searched until 24 February 2021. The structural and functional outcomes were extracted from eligible studies and tabulated. Fifty studies were included: 32 reported structural brain differences between patients with and without fatigue; 14 studies described functional alterations in patients with fatigue compared to patients without it; and four studies showed structural and functional brain alterations in patients. The results revealed structural and functional abnormalities that could correlate to the symptom of fatigue in patients with MS. Several studies reported the differences between patients with fatigue and patients without fatigue in terms of conventional magnetic resonance imaging (MRI) outcomes and brain atrophy, specifically in the thalamus. Functional studies showed abnormal activation in the thalamus and in some regions of the sensorimotor network in patients with fatigue compared to patients without it. Patients with fatigue present more structural and functional alterations compared to patients without fatigue. Specifically, abnormal activation and atrophy of the thalamus and some regions of the sensorimotor network seem linked to fatigue.

Purpose: Given the increased level of fatigue frequently reported by patients with Parkinson's disease (PD), this study investigated the interaction between central and peripheral components of neuromuscular fatigue (NF) in this population compared with healthy peers., Methods: Changes in maximal voluntary activation (ΔVA, central fatigue) and potentiated twitch force (ΔQtw,pot, peripheral fatigue) pre-post exercise were determined via the interpolated twitch technique in 10 patients with PD and 10 healthy controls (CTRL) matched for age, sex, and physical activity. Pulmonary gas exchange, femoral blood flow, and quadriceps EMG were measured during a fatiguing exercise (85% of peak power output [PPO]). For a specific comparison, on another day, CTRL repeat the fatiguing test matching the time to failure (TTF) and PPO of PD., Results: At 85% of PPO (PD, 21 ± 7 W; CTRL, 37 ± 22 W), both groups have similar TTF (~5.9 min), pulmonary gas exchange, femoral blood flow, and EMG. After this exercise, the maximal voluntary contraction (MVC) force and Qtwpot decreased equally in both groups (-16%, P = 0.483; -43%, P = 0.932), whereas VA decreased in PD compared with CTRL (-3.8% vs -1.1%, P = 0.040). At the same PPO and TTF of PD (21 W; 5.4 min), CTRL showed a constant drop in MVC, and Qtwpot (-14%, P = 0.854; -39%, P = 0.540), instead VA decreased more in PD than in CTRL (-3.8% vs -0.7%, P = 0.028)., Conclusions: In PD, central NF seems exacerbated by the fatiguing task which, however, does not alter peripheral fatigue. This, besides the TTF like CTRL, suggests that physical activity may limit NF and counterbalance PD-induced degeneration through peripheral adaptations., (Copyright © 2021 by the American College of Sports Medicine.)

Muscle fatigue induced by voluntary exercise, which requires central motor drive, causes central fatigue that impairs endurance performance of a different, nonfatigued muscle. This study investigated the impact of quadriceps fatigue induced by electrically induced (no central motor drive) contractions on single-leg knee-extension (KE) performance of the subsequently exercising ipsilateral quadriceps. On two separate occasions, eight males completed constant-load (85% of maximal power-output) KE exercise to exhaustion. In a counterbalanced manner, subjects performed the KE exercise with no pre-existing quadriceps fatigue in the contralateral leg on one day (No-PreF), whereas on the other day, the same KE exercise was repeated following electrically induced quadriceps fatigue in the contralateral leg (PreF). Quadriceps fatigue was assessed by evaluating pre- to postexercise changes in potentiated twitch force (ΔQ tw,pot ; peripheral fatigue), and voluntary muscle activation (ΔVA; central fatigue). As reflected by the 57 ± 11% reduction in electrically evoked pulse force, the electrically induced fatigue protocol caused significant knee-extensors fatigue. KE endurance time to exhaustion was shorter during PreF compared with No-PreF (4.6 ± 1.2 vs 7.7 ± 2.4 min; P < 0.01). Although ΔQ tw,pot was significantly larger in No-PreF compared with PreF (-60% vs -52%, P < 0.05), ΔVA was greater in PreF (-14% vs -10%, P < 0.05). Taken together, electrically induced quadriceps fatigue in the contralateral leg limits KE endurance performance and the development of peripheral fatigue in the ipsilateral leg. These findings support the hypothesis that the crossover effect of central fatigue is mainly mediated by group III/IV muscle afferent feedback and suggest that impairments associated with central motor drive may only play a minor role in this phenomenon.