Roberts MD, Bamman MM, Hornberger TA
… +11 more, Mackey AL, Derave W, Atherton PJ, Phillips SM, Schoenfeld BJ, Nader GA, Hecksteden A, Hulmi JJ, Sillanpää E, Libardi CA, Ahtiainen JP
J Appl Physiol (1985)
· 2026 Jun · PMID 42172438
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The Inter-Individual Variation in Resistance Training Response Conference was hosted at the University of Jyväskylä, Finland November 19-21, 2025. This paper summarizes key themes that emerged across lectures and discuss...The Inter-Individual Variation in Resistance Training Response Conference was hosted at the University of Jyväskylä, Finland November 19-21, 2025. This paper summarizes key themes that emerged across lectures and discussions. First, resistance training induces multidimensional adaptations at the tissue, muscle fiber, and ultrastructural levels, including radial muscle fiber hypertrophy through increased myofibril number, longitudinal growth through sarcomere addition throughout the length (not ends) of muscle fibers, and metabolic adaptations that emulate other models of rapid cell growth. Second, training program variables including weekly sets, volume-load, rest interval duration, and training proximity to failure meaningfully influence hypertrophic outcomes in the general population, whereas exercise selection can be flexible. Third, age as well as molecular signatures before and in response to training influence interindividual response heterogeneity. Finally, while interindividual variability in observed hypertrophic responses is considerable, delineating true inter-individual variability from random variation remains challenging. Hence, study design considerations that can be thoughtfully applied to enhance rigor include repeat validation trials, unilateral within-subject designs, minimum clinically important difference thresholds, and multivariate composite responder classifications. This paper aims to summarize conference highlights while also providing meaningful implications for both researchers and practitioners and advancing current thinking on heterogeneity in the resistance training response.
Experimental work in amphibian skeletal muscle and modeling studies have demonstrated that intramuscular fluid volume is an important determinant of the passive force that develops during lengthening. However, this effec...Experimental work in amphibian skeletal muscle and modeling studies have demonstrated that intramuscular fluid volume is an important determinant of the passive force that develops during lengthening. However, this effect has yet to be investigated in mammalian skeletal muscle. Therefore, we exposed isolated mouse soleus and extensor digitorum longus (EDL) muscles to a graded series of hypotonic solutions to promote fluid uptake while measuring passive force development, muscle mass, and two-dimensional (2-D) projected muscle area. Normalized to the tension measured at 1.2 in isotonic Ringer's solution, the relative passive forces in the soleus were 1.14, 1.31, 1.52, and 1.92 in 70%, 60%, 55%, and 50% relative tonicity, respectively. Comparable values for the EDL were 1.13, 1.78, and 2.10 in 70%, 60%, and 55% relative tonicity, respectively. In both muscles, increases in passive force were accompanied by increases in mass and projected area. We also investigated the effect of muscle tension on fluid uptake. Soleus muscles left slack and allowed to shorten when exposed to a hypotonic solution gained much more mass compared with muscles held at the predicted length for maximal active force production, which suggests that at this length water uptake is limited by the buildup of hydrostatic pressure. Our findings support the hypothesis that in mammalian muscle, intramuscular fluid volume is an important determinant of passive force development. These results could have implications for human movement performance, where muscle volume change has been observed in vivo. Our data suggest that intramuscular fluid volume is a determinant of passive force development in mammalian skeletal muscle. The amount of fluid a muscle takes up, and the associated passive force increase, may be fiber-type and muscle-dependent. In addition, we show that there may be an effect of hydrostatic pressure on fluid uptake, with muscles experiencing no tension taking up more fluid than muscles in tension. Together, these findings may have movement performance applications.
Mallette JH, Crudup BF, Oudomrath Speyrer A
… +4 more, Nabors HM, Willis AT, Rawls AZ, Alexander BT
J Appl Physiol (1985)
· 2026 Jun · PMID 42154735
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The biological effects of chronic estrogen supplementation on renal function and injury with aging in men are unknown. Using an experimental model of feminizing hormone therapy (FHT) induced by 17β-estradiol (E2) (5 mg/k...The biological effects of chronic estrogen supplementation on renal function and injury with aging in men are unknown. Using an experimental model of feminizing hormone therapy (FHT) induced by 17β-estradiol (E2) (5 mg/kg sc) supplementation plus castration (CTX) in the male Sprague-Dawley rat starting at 13-15 mo of age, equivalent to a late 30- to 40-yr-old man, we tested the hypothesis that FHT is associated with impaired renal function and renal injury with aging associated with activation of the renin angiotensin system (RAS). However, 24-h creatinine excretion, plasma creatinine, and creatinine clearance did not differ in E2 + CTX compared with Control by 22-24 mo of age, or following 9 mo of FHT. Lean mass was significantly reduced in E2 + CTX vs. Control, but creatinine clearance adjusted to lean mass did not differ. Serum cystatin C, a more reliable biomarker for renal function, was unchanged; urinary cystatin C was reduced, suggesting no renal impairment. However, cystatin C clearance was reduced in E2 + CTX vs. Control, suggesting decreased renal filtration. Proteinuria, urinary kidney injury molecule-1 (KIM-1; a marker of proximal tubule injury), and glomerular injury score were significantly reduced in E2 + CTX vs. Control; however, albuminuria did not differ. Renal angiotensinogen mRNA expression was significantly decreased in E2 + CTX, whereas urinary angiotensinogen, renal renin, and renal angiotensin type 1 receptor mRNA expression did not differ. Collectively, these results suggest that the biological effects of FHT in the aging male are not associated with increased renal injury or inappropriate activation of the RAS; whether renal function is altered remains unclear. Whether enhanced renal risk is associated with chronic estrogen supplementation in the aging male is unknown. Using an experimental model of feminizing hormone therapy (FHT), 17β-estradiol (E2) plus castration (CTX) in male rats initiated after 1 yr of age, renal injury was not increased compared with age-matched male Controls. Whether renal function was impaired remains unclear, highlighting the need to establish more accurate methods to assess the biological effects of FHT on renal function.
Performance during motor activities, such as wheelchair riding, cycling, rowing, and speed skating, depends critically on the average mechanical power output (AMPO) produced by the muscles. To maximize short-duration per...Performance during motor activities, such as wheelchair riding, cycling, rowing, and speed skating, depends critically on the average mechanical power output (AMPO) produced by the muscles. To maximize short-duration performance, limb movements should allow muscles to deliver maximal AMPO. However, it is unclear which movement maximizes AMPO of human muscle. In this study, we employed a Hill-type muscle-tendon-complex (MTC) model to predict the maximally attainable AMPO of human m. quadriceps femoris for various imposed periodic knee joint movements. Based on these predictions, we selected one set of conditions predicted to yield identical maximally attainable AMPO despite substantial variations in knee joint movements and another set of conditions predicted to yield substantial variations in maximally attainable AMPO. In the experiment, periodic knee joint movements were fully imposed by a knee dynamometer. Participants were instructed to maximize AMPO and, to this end, received visual feedback on their cumulative mechanical work throughout each cycle. Experimental data closely matched predictions derived from the Hill-type MTC model, confirming the validity of the model. Model predictions showed a substantial influence of knee joint movement on the maximally attainable AMPO. Specifically, predictions revealed a strong interaction between cycle frequency and knee joint excursion: increasing one necessitates a decrease in the other to maximize AMPO. Even more interestingly, m. quadriceps femoris should spend about 80% of the cycle duration while shortening, independent of cycle frequency and/or knee joint excursion. We examined how knee joint movements influence the maximally attainable average mechanical power output (AMPO) of human quadriceps femoris under all-out (sprint) conditions. Experimental dynamometry measurements showed strong correlation with predictions from a Hill-type muscle-tendon-complex model. Further model exploration revealed that cycle frequency and joint excursion interact: increasing one requires reducing the other to maximize AMPO. Furthermore, to maximize AMPO, quadriceps should spend ∼80% of each cycle shortening, independent of cycle frequency and/or joint excursion.
Oral contraceptive pills (OCPs) are one of the most prescribed medications, yet we lack an understanding of whether and how OCPs affect nonreproductive tissues. Given the well-documented effects of sex hormones on skelet...Oral contraceptive pills (OCPs) are one of the most prescribed medications, yet we lack an understanding of whether and how OCPs affect nonreproductive tissues. Given the well-documented effects of sex hormones on skeletal muscle, including on muscle mass, regeneration, and recovery, our review was aimed at assessing the impact of OCPs on skeletal muscle physiology in female humans and animals. We performed a literature search, title through full text screening, and citation search in accordance with PROSPERO guidelines. Rigor and reproducibility were assessed using the Modified Downs and Black Checklist. Meta-analyses were performed to assess the impact of OCPs on skeletal muscle outcomes. Although our search included both clinical and preclinical studies, the 40 included studies were all clinical, with no identified preclinical studies. Studies focused on young (20-30 yr) sedentary to active females with a healthy BMI (18-27 kg/m) and included primarily strength and serum-based outcomes. All studies were retrospective and level III evidence. Notably, despite this literature spanning from the 1990s to 2025, rigor was in the 69th ± 6.5 percentile, and there was no correlation with rigor and year of publication. Meta-analyses did not detect an effect of OCPs on examined outcome measures; however, heterogeneity was high, suggesting the lack of rejection of the null hypothesis may be driven by variations in studies, making it challenging to draw conclusions. Taken together, we recommend prospective preclinical and well-controlled clinical studies to examine the impact of OCPs on skeletal muscle in the setting of injury, disease, and varying demographics. Our ultimate goal is to understand sex-based differences in skeletal muscle health and empower females with reliable information to inform decisions about their health. This systematic review and meta-analysis was a step toward the goal of understanding the role of OCPs on skeletal muscle health.
The latency between neural drive to a muscle and the resulting force production during continuous contractions is described by the neuromechanical delay (NMD). NMD shortens with increasing contraction intensity and speed...The latency between neural drive to a muscle and the resulting force production during continuous contractions is described by the neuromechanical delay (NMD). NMD shortens with increasing contraction intensity and speed, varies between muscle groups and fascicle lengths, and lengthens under pain sensation. However, it remains unclear how NMD changes during fatigue. We investigated the NMD of the vastii muscles during a sustained sinusoidal contraction performed to exhaustion. Ten healthy adults (9 males) performed maximum voluntary contractions (pre-MVCs), the biofeedback-controlled contraction to exhaustion at a mean force of 30% MVC, and a post-MVC. High-density electromyographic signals were recorded from the vastii muscles and decomposed into motor unit discharge timings. Cross-correlation between neural drive and force was used to determine NMD as the time lag between the two signals. We did not find any differences in neural drive measures or NMD between muscles ( > 0.05). Post-MVC force was significantly reduced by 19% compared with pre-MVC ( < 0.001). NMD increased from 113 (±19) to 168 (±16) ms from the initial 10% to 100% of exhaustion time ( < 0.001). The observed NMD prolongation likely reflects slowed and diminished force transmission due to fatigue-induced accumulation of myofibrillar metabolites, which alter twitch characteristics and mechanical properties of the motor units. Prolongation of the NMD may serve as a key indicator of fatigue, as delays in action potential transmission to force production can generate inhomogeneous muscle forces, thereby potentially increasing the risk of injury. This is the first study to demonstrate that the latency between neural drive and muscle force production lengthens with fatigue during voluntary contractions. Although prior research reported fatigue-related increases in electromechanical delay, these findings come from electrically evoked contractions or the initiation of voluntary contractions from resting muscle. Our approach enables the analysis of neural and force signals during naturally controlled muscle contractions, offering new insight into fatigue-induced changes in neuromuscular function under physiological conditions.
Aging, cardiorespiratory fitness, and habitual physical activity influence thermoregulation and cognition, yet their combined impact during prolonged extreme heat exposure is not well understood. This study investigated...Aging, cardiorespiratory fitness, and habitual physical activity influence thermoregulation and cognition, yet their combined impact during prolonged extreme heat exposure is not well understood. This study investigated how these factors influence thermal strain and cognitive performance across the adult lifespan under extreme heat stress. Sixty-one participants (27 females; 20-79 yr) wore an accelerometer for 7 days, completed a graded exercise test to determine peak oxygen uptake (V̇o), and underwent a 6-h heat exposure (43°C, 25% relative humidity) with episodic exercise to simulate daily living tasks. Rectal (T) and skin temperature, heart rate, whole body sweat rate, and cognitive performance (episodic memory, executive function, attention, and processing speed) were measured. Time, age, V̇o, moderate-vigorous physical activity (MVPA) level, and sex were entered into linear mixed-effects models (mean [95% CI]). Advancing age exacerbated the rise of T (per decade: 0.08°C [0.04, 0.13], < 0.01) and reduced whole body sweating (per decade: -6 g·m·h [-10, -1], < 0.01). Cognitive performance reduced with advancing age, independent of heat exposure ( < 0.01). Higher cardiorespiratory fitness improved whole body sweat rate (per 10 mL·kg·min: 11 g·m·h [2, 19], = 0.01) and reduced end-exposure heart rate (per 10 mL·kg·min: -4 beats/min [-8, -1], = 0.03). Weekly MVPA and sex showed minimal association with outcome variables. Across adulthood, advancing age exacerbated the rise in T and lowered whole body sweating during a 6-h extreme heat exposure. Cardiorespiratory fitness improved whole body sweating but did not offset age-related increases in T. Therefore, physiological strain during extreme heat exposure develops progressively across the lifespan, with cardiorespiratory fitness moderating, but not preventing, age-related susceptibility. Advancing age is associated with progressive increases in the rise in core temperature during extreme heat exposure, and this trajectory is evident across the entire adult lifespan rather than emerging only in older adults. Thermoregulatory capacity declines steadily with each decade, leading to greater thermal strain even in mid-adulthood. Although higher cardiorespiratory fitness enhances sweating, it does not eliminate the age-related increase in core temperature, underscoring that heat vulnerability may develop gradually throughout adulthood.
Limb immobilization leads to a rapid and pronounced loss of muscle strength and size. Cross-education, contralateral resistance training of the nonimmobilized limb, has emerged as a resistance training strategy to mitiga...Limb immobilization leads to a rapid and pronounced loss of muscle strength and size. Cross-education, contralateral resistance training of the nonimmobilized limb, has emerged as a resistance training strategy to mitigate deficit in the immobilization limb. A systematic review and three-level hierarchical meta-analysis were conducted (eight studies were included; = 189) to quantify the effects of cross-education on strength and muscle mass during unilateral upper limb immobilization in healthy participants, examining the influence on training modality, muscle specificity, and immobilization model. Standardized mean change effect sizes (SMCR, Hedges' ) were calculated for strength and muscle size. Cross-education attenuated strength loss compared with immobilization alone ( 0.53, < 0.001), with effect magnitude moderated by immobilization location and training modality. Proximal immobilization yielded greater attenuation (overall: 0.62; eccentric: 0.82; concentric-eccentric: 0.68) than distal immobilization (overall: 0.42; eccentric: 0.34; and isometric: 0.63). Regarding muscle size, cross education produced a small preservation effect in the immobilized limb ( 0.19, = 0.01). This effect was only evident in proximal immobilization ( 0.40) compared with distal ( = 0.06). Strong positive associations were observed between adaptations in the trained and immobilized limbs for strength ( = 0.79) and muscle size ( = 0.81). These findings indicate that cross-education attenuates losses in muscle strength and size during immobilization. However, these results should be interpreted with caution due to the varying risk of bias among the included studies.
Achilles tendon rupture impairs the functional performance of the triceps surae muscle-tendon unit. However, long-term effects of different rehabilitation programs on these impairments remain unclear. This study evaluate...Achilles tendon rupture impairs the functional performance of the triceps surae muscle-tendon unit. However, long-term effects of different rehabilitation programs on these impairments remain unclear. This study evaluated the long-term effects of early rehabilitation versus cast immobilization after Achilles tendon repair. We also examined whether the uninjured side could serve as a reference for the "healthy" side. Males with previous Achilles tendon rupture ( = 20) and a group of healthy male controls (CTR; = 10) participated. Participants with Achilles tendon rupture included a short-term physical therapy group (STPT; = 10) and a plaster cast group (PC; = 10). Triceps surae morphology and ankle functionality were compared among groups. No between-group differences were found in the patient-reported outcomes. The injured side presented lower heel rise height, plantar flexors strength, gastrocnemius medialis thickness, calf volume, and shorter fascicle length than CTR. On the injured side, the STPT preserved ankle range of motion and showed greater plantar flexion and total range of motion than the PC. We used a computational model that demonstrated that tendon elongation was the main determinant of heel rise height deficit. The uninjured side presented lower heel rise height than the CTR group. Despite favorable patient-reported outcomes, long-term structural and functional deficits persist after Achilles tendon rupture, regardless of rehabilitation approach. Findings suggest that the rehabilitation programs used did not fully restore muscle-tendon function and highlight limitations of using the uninjured side as a control. This study compares early mobilization and plaster cast rehabilitation after Achilles tendon rupture, with surgeries performed by a single surgeon. We demonstrate that long-term structural and functional deficits persist 2 yr after Achilles tendon rupture, regardless of rehabilitation type. With a computational model, we investigated the mechanisms underlying heel-rise deficits, quantifying structural contributions. Including a healthy control group revealed that the uninjured side also shows impairments, calling into question its use as a reference in clinical and research settings.
This study sought to investigate the cardiac consequences of undertaking 12 and 24 h of intense cycling as part of two successful world record-setting attempts in a former professional ultra-endurance athlete (12 h attem...This study sought to investigate the cardiac consequences of undertaking 12 and 24 h of intense cycling as part of two successful world record-setting attempts in a former professional ultra-endurance athlete (12 h attempt: March 2017, aged 41 yr; 24 h attempt: March 2018, aged 42 yr). The athlete was comprehensively evaluated before and at several timepoints following both attempts using cardiac imaging [echocardiography, rest, and exercise cardiac magnetic resonance imaging (CMR)], cardiac biomarkers [B-type natriuretic peptide (BNP) and cardiac troponin-I (cTnI)], and clinical evaluation. Following the 12 h attempt, the athlete was physically exhausted but demonstrated no signs of respiratory distress or heart failure. Immediately postattempt, BNP (166 ng/L) and cTnI (64 ng/L) were moderately increased, whereas left ventricular (LV) and right ventricular (RV) strain (LV: -12.2%; RV: -13.4%) and ejection fraction (LV: 43%; RV: 43%) were moderately reduced. However, all parameters were recovered within 14 days of the attempt. Following the 24 h attempt, the athlete was in acute respiratory distress and showed signs of acute pulmonary edema. This coincided with pronounced biomarker elevations (BNP: 561 ng/L and cTnI: 394 ng/L) and marked reductions in myocardial strain (LV: -14.2%; RV: -13.8%) and biventricular ejection fraction (LV: 37%; RV: 32%). Cardiac function only partially recovered 18 days postattempt but had completely normalized by 5 mo postattempt. Overall, these findings provide the most definitive illustration of an exercise dose threshold that resulted in acute heart failure in a highly trained endurance athlete. The absence of persistent myocardial injury highlights the resilience of the heart to acute stress. This case study of a highly trained ultra-endurance athlete performing two world-record setting 12 and 24 h cycling bouts provides the most definitive illustration that a sufficiently intense and prolonged dose of exercise (in this case, 24 h of intense cycling) can result in acute heart failure. The absence of persistent myocardial injury highlights the remarkable resilience of the cardiovascular system to acute stress and reinforces the importance of adequate recovery following prolonged and intensive endurance exercise bouts.
Most therapeutic applications of peripheral nerve electrical stimulation do not measure resulting nerve activation. A fixed axon population is often assumed to stably respond to electrical stimulation, with nerve firing...Most therapeutic applications of peripheral nerve electrical stimulation do not measure resulting nerve activation. A fixed axon population is often assumed to stably respond to electrical stimulation, with nerve firing rates increasing proportionally to stimulation frequency. We investigated this assumption in peripheral somatosensory fibers of 10 healthy human participants, measuring evoked compound action potentials (CAPs) as a representation of nerve population firing rate. One-second stimulus trains at frequencies 25 to 200 Hz were repeated with interstimulus intervals of 0.1 to 6 s. Over the duration of a 1-s stimulus train, CAP amplitudes showed mean declines of nearly 40% for 200-Hz stimulation frequency and 20% for 100 Hz, compared to less than 10% for 25 and 50 Hz, with the majority of these decreases happening within 0.2 s of stimulation onset. CAP amplitude declines were mainly associated with stimulation frequency and short timescales, compared to longer timescales across dozens of repeated stimulus trains (mean decline of 4.9% and range of 1.03 to 11.6% across parameter combinations). These findings show that the assumption of axon populations responding stably to electrical stimulation is untrue. CAP amplitude declines showed large variation between different participants, emphasizing the need to tailor dosing of electrical stimulation for individual users using objective physiological measures. This study contributes to understanding the effects of electrical stimulation on nerve responsiveness via compound action potential (CAP) measurements. Contrary to existing assumptions, sensory axons were unable to entrain stimulation frequencies above 50 Hz. There was significant variation in response declines between participants, suggesting that electrical stimulation therapies may require dose monitoring and tailoring for different individuals.
We previously audited the over its entire history to assess the involvement of female individuals as research participants and manuscript authors. Here, we assess potential factors influencing the inclusion of female in...We previously audited the over its entire history to assess the involvement of female individuals as research participants and manuscript authors. Here, we assess potential factors influencing the inclusion of female individuals as authors and research participants. We previously found that, over the 28,000+ papers published from 1948 to 2023, 20% of authors were female individuals. In the present analysis, we found that this percentage was very similar for human research (20%), animal model (20%), and nonexperimental papers (17%). Over this history, papers with three or more male authors accounted for the majority of papers with at least one male author, whereas the majority of papers with at least one female author had a single female author. As a baseline, when a manuscript has all male authors, female individuals represent 21% of research participants. However, with at least one female author on a manuscript, 42% of research participants were female individuals. There is also a dose-response relationship: with one female author on a paper, female individuals account for 39% of the participants, increasing to 43% with two female authors and to 46% with three or more female authors. In manuscripts with male first/last authors, female individuals represent 31% of research participants, whereas with a female first/last author, 44% of research participants were female individuals. Furthermore, when there were only male research participants in a study, only 16% of the authors were female individuals, whereas when only female research participants were included in a study, the percentage of female authors was over twice as high at 35%. Thus, herein, some factors are identified, mostly the number of female authors on a manuscript, that have a substantial effect on the inclusion of female research participants in applied physiology research publications. We previously quantified the underrepresentation of female research participants and manuscript authors across the entire history of the . In this paper, we quantify the interactions between female research participants and manuscript authors, finding that the greater the number of female authors on a manuscript, the higher is the female research participant rate in that study. Furthermore, in studies with only female research participants, the number of female authors is also higher.
High-intensity interval training (HIIT) and continuous endurance exercise (END) induce distinct neuromuscular adaptations, with END particularly enhancing fatigue resistance during sustained submaximal contractions. Howe...High-intensity interval training (HIIT) and continuous endurance exercise (END) induce distinct neuromuscular adaptations, with END particularly enhancing fatigue resistance during sustained submaximal contractions. However, the motor unit (MU) mechanisms underlying these effects remain unclear. This study investigated MU firing adaptations associated with changes in time to task failure following END and HIIT. Sixteen healthy men were randomly assigned to END or HIIT ( = 8/group) and completed six sessions over 14 days. HIIT involved 8-12 × 60-s intervals at 100% peak power output, separated by a 75-s recovery; END involved 90-120 min of continuous cycling at ∼65% peak oxygen uptake (V̇o). Before and after training, participants performed a nonfatiguing isometric contraction at 50% maximal voluntary contraction (MVC), followed by a sustained contraction at 30% MVC until failure, while high-density surface EMG signals were recorded from the vasti muscles. Signals were decomposed, and MUs were tracked across sessions. MU firing rates displayed a biphasic response to fatigue: an initial decline (first phase) followed by a later increase (second phase). Postintervention, only the END group increased time-to-task failure and delayed the onset of the second phase ( = 0.021), which correlated with time to failure ( = 0.70). The END group also showed less attenuation in firing rate at failure (50% vs. 30% MVC difference: END = 0.56 Hz; HIIT = 2.8 Hz; = 0.011), which was also associated with total endurance time ( = 0.72). These findings suggest that END-induced fatigue resistance is associated with specific MU firing adaptations that enhance the central nervous system's ability to optimise MU recruitment and firing dynamics during fatigue development. Two weeks of endurance training (END), but not high-intensity interval training (HIIT), prolonged time to task failure during sustained submaximal contractions. This improvement in performance was linked to distinct motor unit adaptations, delayed discharge rate increase, and reduced firing rate attenuation that explained ∼50% of performance gains. Short-term END thus elicits unique neuromuscular changes that enhance fatigue resistance at low-to-moderate intensities.
Inspiratory effort is associated with the recruitment of extra-diaphragmatic muscles, including parasternal intercostal muscles (PIMs). The mechanical behavior of PIM and its relationship to indices of inspiratory effort...Inspiratory effort is associated with the recruitment of extra-diaphragmatic muscles, including parasternal intercostal muscles (PIMs). The mechanical behavior of PIM and its relationship to indices of inspiratory effort in humans remains poorly characterized. We investigated whether PIM stiffening, assessed using ultrafast ultrasound shear wave elastography (SWE), tracks inspiratory effort breath-by-breath during graded inspiratory loading. Fourteen healthy adults (9 men and 5 women) were studied during quiet breathing and inspiratory threshold loading at 10%, 20%, 30%, and 40% of maximal inspiratory pressure. Inspiratory changes in PIM shear modulus (Δµ) were quantified from SWE and related to esophageal (ΔP̄es) and transdiaphragmatic (ΔP̄di) pressure swings, pressure-time products (PTP̄es and PTP̄di), and crural diaphragm electromyography (EAdi). The ability of Δµ to detect increased inspiratory effort was evaluated per breath using receiver operating characteristic (ROC) analysis. Inspiratory loading induced progressive increases in PIM stiffening (Δµ: 10.2 ± 7.4 to 24.0 ± 15.9 kPa, < 0.001). Δµ showed strong within-subject correlations with ΔP̄es and ΔP̄di ( = 0.72 and = 0.68, respectively; both < 0.0001) and moderate correlations with PTP̄es and PTP̄di ( = 0.50 and = 0.49, respectively; both < 0.001). Δµ was also moderately correlated with EAdi ( = 0.45, < 0.001). Breath-by-breath Δµ discriminated breaths with increased inspiratory effort with a pooled ROC area under the curve of 0.78. PIM stiffening increased proportionally with inspiratory load and was correlated with established pressure- and activation-based indices of inspiratory effort. These findings define the mechanical behavior of the PIM during loaded breathing and identify PIM stiffening as a noninvasive mechanical readout of increased inspiratory effort in humans. Using ultrasound shear wave elastography, we tracked parasternal intercostal muscle stiffness breath-by-breath during quiet breathing and graded inspiratory threshold loading. Changes in parasternal intercostal muscle stiffness increased progressively with load and were closely associated with indices of inspiratory effort from pressure recordings and diaphragm electrical activity. Stiffness measurements identified breaths with elevated inspiratory effort and may serve as a practical, noninvasive mechanical readout of global inspiratory effort, with potential relevance for respiratory disease assessment and assisted-ventilation monitoring.
Skeletal unloading during microgravity rapidly disrupts bone and metabolic homeostasis, yet sex-specific physiological responses remain poorly characterized. Dry immersion (DI), a ground-based analogue of microgravity, p...Skeletal unloading during microgravity rapidly disrupts bone and metabolic homeostasis, yet sex-specific physiological responses remain poorly characterized. Dry immersion (DI), a ground-based analogue of microgravity, provides a model to investigate early determinants of unloading-induced bone deconditioning. We assessed sex differences in serum biochemical markers of bone and energy metabolism during two 5-day European Space Agency DI campaigns (VIVALDI 1 and 2) involving healthy males ( = 19) and females ( = 18). DI induced rapid alterations in bone remodeling in both sexes, characterized by increased bone resorption. Tartrate-resistant acid phosphatase isoform 5b (TRAP5b) increased more in females than in males (+22% vs. +11%; = 0.02), whereas crosslinked C-terminal telopeptide of type I collagen (CTX) rose (+10%; < 0.05) only in females at DI completion. Bone formation markers declined similarly in both sexes, including procollagen type I N-terminal propeptide (PINP) (-22% males, -19% females; < 0.001), osteocalcin, and carboxylated osteocalcin, whereas bone alkaline phosphatase increased, indicating dissociation between new matrix formation and mineralization. Periostin decreased in both sexes but more markedly in females (-29%; < 0.001) and did not recover post-DI. Calcium increased transiently at DI-48 h ( < 0.001), whereas parathyroid hormone (PTH) declined throughout immersion and recovery ( < 0.001). IGF-1 (+8%; < 0.001) and visfatin (+63% males, +78% females; < 0.001) increased, with visfatin normalizing post-DI only in females. Overall, although both sexes exhibited early bone deconditioning, females showed greater and more persistent resorption and periostin reduction, suggesting a faster progression toward bone loss. These early sex-specific responses identify potential biomarker that may enhance mechanistic understanding and guide the development of targeted countermeasures for spaceflight- and immobilization-related bone loss. Dry immersion induces rapid bone deconditioning in both sexes, but females show greater skeletal sensitivity to unloading, with stronger resorptive increases [tartrate-resistant acid phosphatase isoform 5b (TRAP5b), crosslinked C-terminal telopeptide of type I collagen (CTX)] and a more pronounced periosteal decline (periostin) that does not recover after immersion. Concurrent rises in IGF-1 and visfatin are suggestive of coordinated metabolic-skeletal responses. These sex-specific biomarker patterns highlight early physiological differences and may help guide the development of targeted countermeasures for spaceflight and immobilization.