The effects of resistance training on denervated myofibers, senescent cells, and associated protein markers in middle-aged adults.

Denervated myofibers and senescent cells are hallmarks of skeletal muscle aging. However, sparse research has examined how resistance training affects these outcomes. We investigated the effects of unilateral leg extensor resistance training (2 days/week for 8 weeks) on denervated myofibers, senescent cells, and associated protein markers in apparently healthy middle-aged participants (MA, 55 ± 8 years old, 17 females, 9 males). We obtained dual-leg vastus lateralis (VL) muscle cross-sectional area (mCSA), VL biopsies, and strength assessments before and after training. Fiber cross-sectional area (fCSA), satellite cells (Pax7+), denervated myofibers (NCAM+), senescent cells (p16+ or p21+), proteins associated with denervation and senescence, and senescence-associated secretory phenotype (SASP) proteins were analyzed from biopsy specimens. Leg extensor peak torque increased after training (p < .001), while VL mCSA trended upward (interaction p = .082). No significant changes were observed for Type I/II fCSAs, NCAM+ myofibers, or senescent (p16+ or p21+) cells, albeit satellite cells increased after training (p = .037). While >90% satellite cells were not p16+ or p21+, most p16+ and p21+ cells were Pax7+ (>90% on average). Training altered 13 out of 46 proteins related to muscle-nerve communication (all upregulated, p < .05) and 10 out of 19 proteins related to cellular senescence (9 upregulated, p < .05). Only 1 out of 17 SASP protein increased with training (IGFBP-3, p = .031). In conclusion, resistance training upregulates proteins associated with muscle-nerve communication in MA participants but does not alter NCAM+ myofibers. Moreover, while training increased senescence-related proteins, this coincided with an increase in satellite cells but not alterations in senescent cell content or SASP proteins. These latter findings suggest shorter term resistance training is an unlikely inducer of cellular senescence in apparently healthy middle-aged participants. However, similar study designs are needed in older and diseased populations before definitive conclusions can be drawn.

The Forces Generated by Agonist Muscles during Isometric Contractions Arise from Motor Unit Synergies.

The purpose of our study was to identify the low-dimensional latent components, defined hereafter as motor unit modes, underlying the discharge rates of the motor units in two knee extensors (vastus medialis and lateralis, eight men) and two hand muscles (first dorsal interossei and thenars, seven men and one woman) during submaximal isometric contractions. Factor analysis identified two independent motor unit modes that captured most of the covariance of the motor unit discharge rates. We found divergent distributions of the motor unit modes for the hand and vastii muscles. On average, 75% of the motor units for the thenar muscles and first dorsal interosseus were strongly correlated with the module for the muscle in which they resided. In contrast, we found a continuous distribution of motor unit modes spanning the two vastii muscle modules. The proportion of the muscle-specific motor unit modes was 60% for vastus medialis and 45% for vastus lateralis. The other motor units were either correlated with both muscle modules (shared inputs) or belonged to the module for the other muscle (15% for vastus lateralis). Moreover, coherence of the discharge rates between motor unit pools was explained by the presence of shared synaptic inputs. In simulations with 480 integrate-and-fire neurons, we demonstrate that factor analysis identifies the motor unit modes with high levels of accuracy. Our results indicate that correlated discharge rates of motor units that comprise motor unit modes arise from at least two independent sources of common input among the motor neurons innervating synergistic muscles.SIGNIFICANCE STATEMENT It has been suggested that the nervous system controls synergistic muscles by projecting common synaptic inputs to the engaged motor neurons. In our study, we reduced the dimensionality of the output produced by pools of synergistic motor neurons innervating the hand and thigh muscles during isometric contractions. We found two neural modules, each representing a different common input, that were each specific for one of the muscles. In the vastii muscles, we found a continuous distribution of motor unit modes spanning the two synergistic muscles. Some of the motor units from the homonymous vastii muscle were controlled by the dominant neural module of the other synergistic muscle. In contrast, we found two distinct neural modules for the hand muscles.

Motor unit discharge rate modulation during isometric contractions to failure is intensity- and modality-dependent.

The physiological mechanisms determining the progressive decline in the maximal muscle torque production capacity during isometric contractions to task failure are known to depend on task demands. Task-specificity of the associated adjustments in motor unit discharge rate (MUDR), however, remains unclear. This study examined MUDR adjustments during different submaximal isometric knee extension tasks to failure. Participants performed a sustained and an intermittent task at 20% and 50% of maximal voluntary torque (MVT), respectively (Experiment 1). High-density surface EMG signals were recorded from vastus lateralis (VL) and medialis (VM) and decomposed into individual MU discharge timings, with the identified MUs tracked from recruitment to task failure. MUDR was quantified and normalised to intervals of 10% of contraction time (CT). MUDR of both muscles exhibited distinct modulation patterns in each task. During the 20% MVT sustained task, MUDR decreased until ∼50% CT, after which it gradually returned to baseline. Conversely, during the 50% MVT intermittent task, MUDR remained stable until ∼40-50% CT, after which it started to continually increase until task failure. To explore the effect of contraction intensity on the observed patterns, VL and VM MUDR was quantified during sustained contractions at 30% and 50% MVT (Experiment 2). During the 30% MVT sustained task, MUDR remained stable until ∼80-90% CT in both muscles, after which it continually increased until task failure. During the 50% MVT sustained task the increase in MUDR occurred earlier, after ∼70-80% CT. Our results suggest that adjustments in MUDR during submaximal isometric contractions to failure are contraction modality- and intensity-dependent. KEY POINTS: During prolonged muscle contractions a constant motor output can be maintained by recruitment of additional motor units and adjustments in their discharge rate. Whilst contraction-induced decrements in neuromuscular function are known to depend on task demands, task-specificity of motor unit discharge behaviour adjustments is still unclear. In this study, we tracked and compared discharge activity of several concurrently active motor units in the vastii muscles during different submaximal isometric knee extension tasks to failure, including intermittent vs. sustained contraction modalities performed in the same intensity domain (Experiment 1), and two sustained contractions performed at different intensities (Experiment 2). During each task, motor units modulated their discharge rate in a distinct, biphasic manner, with the modulation pattern depending on contraction intensity and modality. These results provide insight into motoneuronal adjustments during contraction tasks posing different demands on the neuromuscular system.

Differential utilisation of subcellular skeletal muscle glycogen pools: a comparative analysis between 1 and 15 min of maximal exercise.

In skeletal muscle, glycogen particles are distributed both within and between myofibrils, as well as just beneath the sarcolemma. Their precise localisation may influence their degradation rate. Here, we investigated how exercise at different intensities and durations (1- and 15-min maximal exercise) with known variations in glycogenolytic rate and contribution from anaerobic metabolism affects utilisation of the distinct pools. Furthermore, we investigated how decreased glycogen availability achieved through lowering carbohydrate and energy intake after glycogen-depleting exercise affect the storage of glycogen particles (size, numerical density, localisation). Twenty participants were divided into two groups performing either a 1-min (n = 10) or a 15-min (n = 10) maximal cycling exercise test. In a randomised, counterbalanced, cross-over design, the exercise tests were performed following short-term consumption of two distinct diets with either high or moderate carbohydrate content (10 vs. 4 g kg-1 body mass (BM) day-1) mediating a difference in total energy consumption (240 vs. 138 g kg-1 BM day-1). Muscle biopsies from m. vastus lateralis were obtained before and after the exercise tests. Intermyofibrillar glycogen was preferentially utilised during the 1-min test, whereas intramyofibrillar glycogen was preferentially utilised during the 15-min test. Lowering carbohydrate and energy intake after glycogen-depleting exercise reduced glycogen availability by decreasing particle size across all pools and diminishing numerical density in the intramyofibrillar and subsarcolemmal pools. In conclusion, distinct subcellular glycogen pools were differentially utilised during 1-min and 15-min maximal cycling exercise. Additionally, lowered carbohydrate and energy consumption after glycogen-depleting exercise altered glycogen storage by reducing particle size and numerical density, depending on subcellular localisation. KEY POINTS: In human skeletal muscle, glycogen particles are localised in distinct subcellular compartments, referred to as intermyofibrillar, intramyofibrillar and subsarcolemmal pools. The intermyofibrillar and subsarcolemmal pools are close to mitochondria, while the intramyofibrillar pool is at a distance from mitochondria. We show that 1 min of maximal exercise is associated with a preferential utilisation of intermyofibrillar glycogen, and, on the other hand, that 15 min of maximal exercise is associated with a preferential utilisation of intramyofibrillar glycogen. Furthermore, we demonstrate that reduced glycogen availability achieved through lowering carbohydrate and energy intake after glycogen-depleting exercise is characterised by a decreased glycogen particle size across all compartments, with the numerical density only diminished in the intramyofibrillar and subsarcolemmal compartments. These results suggest that exercise intensity influences the subcellular pools of glycogen differently and that the dietary content of carbohydrates and energy is linked to the size and subcellular distribution of glycogen particles.

Low-frequency sounds combined with motor imagery elicits a transient disruption of force performance: A path to neuromotor reprogramming?

The effectiveness of motor imagery (MI) training on sports performance is now well-documented. Recently, it has been proposed that a single session of MI combined with low frequency sound (LFS) might enhance muscle activation. However, the neural mechanisms underlying this effect remain unknown. We set up a test-retest intervention over the course of 2 consecutive days to evaluate the effect of (i) MI training (MI, n = 20), (ii) MI combined with LFS (MI + LFS, n = 20), and (iii) a control condition (CTRL, n = 20) on force torque produced across repeated maximal voluntary contractions of the quadriceps before (Pretest), after (Posttest) and at +12 h (Retention) post-intervention. We collected the integrated electromyograms of the quadriceps muscles, as well as brain electrical potentials during each experimental intervention. In the CTRL group, total force torque decreased from Pretest to Retention and from Posttest to Retention. By contrast, there was an increase between Posttest and Retention in both MI + LFS and MI groups (both ηP2 = 0.03, p < 0.05). Regression analyses further revealed a negative relationship between force performance and EEG activity in the MI + LFS group only. The data support a transient interference of LFS on cortical activity underlying the priming effects of MI practice on force performance. Findings are discussed in relation to the potential for motor reprogramming through MI combined with LFS.

The role of interleukin-10 in mitigating endoplasmic reticulum stress in aged mice through exercise.

Although unfolded protein response (UPR) is essential for cellular protection, its prolonged activation may induce apoptosis, compromising cellular longevity. The aging process increases the endoplasmic reticulum (ER) stress in skeletal muscle. However, whether combined exercise can prevent age-induced ER stress in skeletal muscle remains unknown. Evidence suggests that ER stress may increase inflammation by counteracting the positive effects of interleukin-10 (IL-10), whereas its administration in cells inhibits ER stress and apoptosis. This study verified the effects of aging and combined exercise on physical performance, ER stress markers, and inflammation in the quadriceps of mice. Moreover, we verified the effects of IL-10 on ER stress markers. C57BL/6 mice were distributed into young (Y, 6 mo old), old sedentary (OS, sedentary, 24 mo old), and old trained group (OT, submitted to short-term combined exercise, 24 mo old). To clarify the role of IL-10 in UPR pathways, knockout mice lacking IL-10 were used. The OS mice presented worse physical performance and higher ER stress-related proteins, such as C/EBP homologous protein (CHOP) and phospho-eukaryotic translation initiation factor 2 alpha (p-eIF2α/eIF2α). The exercise protocol increased muscle strength and IL-10 protein levels in OT while inducing the downregulation of CHOP protein levels compared with OS. Furthermore, mice lacking IL-10 increased BiP, CHOP, and p-eIF2α/eIF2α protein levels, indicating this cytokine can regulate the ER stress response in skeletal muscle. Bioinformatics analysis showed that endurance and resistance training downregulated DNA damage inducible transcript 3 (DDIT3) and XBP1 gene expression in the vastus lateralis of older people, reinforcing our findings. Thus, combined exercise is a potential therapeutic intervention for promoting adjustments in ER stress markers in aged skeletal muscle.NEW & NOTEWORTHY Aging elevates endoplasmic reticulum (ER) stress in skeletal muscle, potentially heightening inflammation by opposing interleukin-10 (IL-10) effects. This study found that short-term combined exercise boosted strength and IL-10 protein levels while reducing CHOP protein levels in older mice. In addition, IL-10-deficient mice exhibited increased ER stress markers, highlighting IL-10's role in regulating ER stress in skeletal muscle. Consequently, combined exercise emerges as a therapeutic intervention to elevate IL-10 and adjust ER stress markers in aging.

Estimates of persistent inward currents in lower limb muscles are not different between inactive, resistance-trained, and endurance-trained young males.

Persistent inward currents (PICs) increase the intrinsic excitability of α-motoneurons. The main objective of this study was to compare estimates of α-motoneuronal PICs between inactive, chronic resistance-trained, and chronic endurance-trained young individuals. We also aimed to investigate whether there is a relationship in the estimates of α-motoneuronal PIC magnitude between muscles. Estimates of PIC magnitude were obtained in three groups of young individuals: resistance-trained (n = 12), endurance-trained (n = 12), and inactive (n = 13). We recorded high-density surface electromyography (HDsEMG) signals from tibialis anterior (TA), gastrocnemius medialis (GM), soleus (SOL), vastus medialis (VM), and vastus lateralis (VL). Then, signals were decomposed with convolutive blind source separation to identify motor unit (MU) spike trains. Participants performed triangular isometric contractions to a peak of 20% of their maximum voluntary contraction. A paired-motor-unit analysis was used to calculate ΔF, which is assumed to be proportional to PIC magnitude. Despite the substantial differences in physical training experience between groups, we found no differences in ΔF, regardless of the muscle. Significant correlations of estimates of PIC magnitude were found between muscles of the same group (VL-VM, SOL-GM). Only two correlations (out of 8) between muscles of different groups were found (TA-GM and VL-GM). Overall, our findings suggest that estimates of PIC magnitude from lower-threshold MUs at low contraction intensities in the lower limb muscles are not influenced by physical training experience in healthy young individuals. They also suggest muscle-specific and muscle group-specific regulations of the estimates of PIC magnitude.NEW & NOTEWORTHY Chronic resistance and endurance training can lead to specific adaptations in motor unit activity. The contribution of α-motoneuronal persistent inward currents (PICs) to these adaptations is currently unknown in healthy young individuals. Therefore, we studied whether estimates of α-motoneuronal PIC magnitude are higher in chronically trained endurance- and resistance-trained individuals. We also studied whether there is a relationship between the estimates of α-motoneuronal PIC magnitude of different lower limb muscles.

Time-of-day effects on motor unit firing and muscle contractile properties in humans.

Intrinsic factors related to neuromuscular function are time-of-day dependent, but diurnal rhythms in neural and muscular components of the human neuromuscular system remain unclear. The present study aimed to investigate the time-of-day effects on neural excitability and muscle contractile properties by assessing the firing properties of tracked motor units and electrically evoked twitch muscle contraction. In 15 young adults (22.9 ± 4.7 yr), neuromuscular function was measured in the morning (10:00), at noon (13:30), in the evening (17:00), and at night (20:30). Four measurements were completed within 24 h. The measurements consisted of maximal voluntary contraction (MVC) strength of knee extension, recording of high-density surface electromyography (HDsEMG) from the vastus lateralis during ramp-up contraction to 50% of MVC, and evoked twitch torque of knee extensors by electrical stimulation. Recorded HDsEMG signals were decomposed to individual motor unit firing behaviors and the same motor units were tracked among the times of day, and recruitment thresholds and firing rates were calculated. The number of detected and tracked motor units was 127. Motor unit firing rates significantly increased from morning to noon, evening, and night (P < 0.01), but there were no significant differences in recruitment thresholds among the times of day (P > 0.05). Also, there were no significant effects of time of day on evoked twitch torque (P > 0.05). Changes in the motor unit firing rate and evoked twitch torque were not significantly correlated (P > 0.05). These findings suggest that neural excitability may be affected by the time of day, but it did not accompany changes in peripheral contractile properties in a diurnal manner.NEW & NOTEWORTHY We investigated the variations of tracked motor unit firing properties and electrically evoked twitch contraction during the day within 24 h. The variation of motor unit firing rate was observed, and tracked motor unit firing rate increased at noon, in the evening, and at night compared with that in the morning. The variation in motor unit firing rate was independent of changes in twitch contraction. Motor unit firing rate may be affected by diurnal rhythms.

Reduced inhibition from quadriceps onto soleus after acute quadriceps fatigue suggests Golgi tendon organ contribution to heteronymous inhibition.

Heteronymous inhibition between lower limb muscles is primarily attributed to recurrent inhibitory circuits in humans but could also arise from Golgi tendon organs (GTOs). Distinguishing between recurrent inhibition and mechanical activation of GTOs is challenging because their heteronymous effects are both elicited by stimulation of nerves or a muscle above motor threshold. Here, the unique influence of mechanically activated GTOs was examined by comparing the magnitude of heteronymous inhibition from quadriceps (Q) muscle stimulation onto ongoing soleus electromyographic at five Q stimulation intensities (1.5-2.5× motor threshold) before and after an acute bout of stimulation-induced Q fatigue. Fatigue was used to decrease Q stimulation evoked force (i.e., decreased GTO activation) despite using the same pre-fatigue stimulation currents (i.e., same antidromic recurrent inhibition input). Thus, a decrease in heteronymous inhibition after Q fatigue and a linear relation between stimulation-evoked torque and inhibition both before and after fatigue would support mechanical activation of GTOs as a source of inhibition. A reduction in evoked torque but no change in inhibition would support recurrent inhibition. After fatigue, Q stimulation-evoked knee torque, heteronymous inhibition magnitude and inhibition duration were significantly decreased for all stimulation intensities. In addition, heteronymous inhibition magnitude was linearly related to twitch-evoked knee torque before and after fatigue. These findings support mechanical activation of GTOs as a source of heteronymous inhibition along with recurrent inhibition. The unique patterns of heteronymous inhibition before and after fatigue across participants suggest the relative contribution of GTOs, and recurrent inhibition may vary across persons.

Pharmacokinetics and tolerability of cabotegravir and rilpivirine long-acting intramuscular injections to the vastus lateralis (lateral thigh) muscles of healthy adult participants.

Cabotegravir + rilpivirine administered via intramuscular gluteal injections is the first complete long-acting (LA) regimen approved for maintaining HIV-1 virologic suppression. The vastus lateralis (lateral) thigh muscle could be a potential alternative site of administration in circumstances such as injection site fatigue, intolerability, or contraindication for gluteal administration. Cabotegravir and rilpivirine pharmacokinetics and participant tolerability were evaluated following single intramuscular injections to the lateral thigh. Healthy adult participants received 4 weeks of daily oral cabotegravir (30 mg) and rilpivirine (25 mg), followed by a 10- to 14-day washout and single 3 mL intramuscular injections of cabotegravir LA 600 mg and rilpivirine LA 900 mg to the lateral thigh. Safety, tolerability, and pharmacokinetics were evaluated through 52 weeks post injection. Pharmacokinetic parameters were estimated using non-compartmental analysis. Fifteen participants (female at birth, n = 6) enrolled. Median age was 33 years. Median weight was 93.6 kg. Median body mass index was 31.4 kg/m2. One participant withdrew due to pregnancy after oral dosing before receiving an injection. Plasma concentrations at Weeks 4 and 8 were 15.4- and 5.3-fold above the protein-adjusted 90% inhibitory concentration for cabotegravir and 4.7- and 2.4-fold for rilpivirine, respectively. The most common injection site reactions were pain [28/28 (100%)], induration [15/28 (54%)], and swelling [12/28 (42%)]; 94% were Grade 1 or 2. Cabotegravir and rilpivirine plasma pharmacokinetic profiles observed in this study support further evaluation of thigh administration in target populations of people living with HIV-1. Tolerability of cabotegravir + rilpivirine LA intramuscular lateral thigh injections was similar to gluteal administration.

Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency.

Reversible infantile respiratory chain deficiency (RIRCD) is a rare mitochondrial myopathy leading to severe metabolic disturbances in infants, which recover spontaneously after 6-months of age. RIRCD is associated with the homoplasmic m.14674T>C mitochondrial DNA mutation; however, only ~ 1/100 carriers develop the disease. We studied 27 affected and 15 unaffected individuals from 19 families and found additional heterozygous mutations in nuclear genes interacting with mt-tRNAGlu including EARS2 and TRMU in the majority of affected individuals, but not in healthy carriers of m.14674T>C, supporting a digenic inheritance. Our transcriptomic and proteomic analysis of patient muscle suggests a stepwise mechanism where first, the integrated stress response associated with increased FGF21 and GDF15 expression enhances the metabolism modulated by serine biosynthesis, one carbon metabolism, TCA lipid oxidation and amino acid availability, while in the second step mTOR activation leads to increased mitochondrial biogenesis. Our data suggest that the spontaneous recovery in infants with digenic mutations may be modulated by the above described changes. Similar mechanisms may explain the variable penetrance and tissue specificity of other mtDNA mutations and highlight the potential role of amino acids in improving mitochondrial disease.

Effect of electrical muscle stimulation on cerebrovascular function and cognitive performance.

It is known that electrical muscle stimulation (EMS) can enhance physical function, but its impact on cognition and cerebral hemodynamics is not well understood. Thus, the purpose of this study was to investigate the effects of one EMS session on cerebrovascular function and cognitive performance. The 17 recruited young healthy participants undertook a 25-min session of EMS and a resting control session (Ctrl group) in a random order. Cerebral blood flow velocity (CBFv) in the middle and posterior cerebral arteries (right MCAv and left PCAv, respectively), cerebral oxygenation, cardiac output, and heart rate were measured throughout the sessions, whereas cognitive function was assessed before and after each experimental condition. MCAv, cardiac output, heart rate, and cerebral oxygenation were increased throughout the EMS session, whereas PCAv remained unchanged. In addition, EMS led to improved scores at the Rey auditory verbal learning test-part B and congruent Stroop task versus Ctrl. The present study demonstrates that a single session of EMS may improve cognitive performance and concomitantly increase CBFv and cerebral oxygenation. Therefore, EMS appears to be a valuable surrogate for voluntary exercise and could therefore be advantageously used in populations with severe physical limitations who would not be able to perform physical exercise otherwise.NEW & NOTEWORTHY This study is the first to demonstrate that one session of EMS applied to the quadriceps increases cerebral blood flow velocity and cerebral oxygenation, which are pivotal factors for brain health. Thus, EMS has the potential to be used as an interesting option in rehabilitation to increase cerebral perfusion and defend if not improve cognitive function sustainably for people with severe physical limitations who would not be able to perform physical exercise voluntarily.

Alleviation of peripheral sensitization by quadriceps insertion of cog polydioxanone filaments in knee osteoarthritis rats.

A recently established therapeutic strategy, involving the insertion of biodegradable cog polydioxanone filaments into the quadriceps muscles using the Muscle Enhancement and Support Therapy (MEST) device, has demonstrated significant efficacy in alleviating knee osteoarthritis (OA) pain. This study investigated changes in peripheral sensitization as the potential mechanism underlying MEST-induced pain relief in monoiodoacetate (MIA) induced OA rats. The results revealed that MEST treatment potently reduces MIA-induced sensitization of L3/L4 dorsal root ganglion (DRG) neurons, the primary nociceptor pathway for the knee joint. This reduction in DRG sensitization, as elucidated by voltage-sensitive dye imaging, is accompanied by a diminished overexpression of TRPA1 and NaV1.7, key nociceptor receptors involved in mechanical pain perception. Importantly, these observed alterations strongly correlate with a decrease in mechanically-evoked pain behaviors, providing compelling neurophysiological evidence that MEST treatment alleviates OA pain by suppressing peripheral sensitization.

The reliability and validity of rapid transcranial magnetic stimulation mapping for muscles under active contraction.

Rapid mapping is a transcranial magnetic stimulation (TMS) mapping method which can significantly reduce data collection time compared to traditional approaches. However, its validity and reliability has only been established for upper-limb muscles during resting-state activity. Here, we determined the validity and reliability of rapid mapping for non-upper limb muscles that require active contraction during TMS: the masseter and quadriceps muscles. Eleven healthy participants attended two sessions, spaced two hours apart, each involving rapid and 'traditional' mapping of the masseter muscle and three quadriceps muscles (rectus femoris, vastus medialis, vastus lateralis). Map parameters included map volume, map area and centre of gravity (CoG) in the medial-lateral and anterior-posterior directions. Low to moderate measurement errors (%SEMeas = 10-32) were observed across muscles. Relative reliability varied from good-to-excellent (ICC = 0.63-0.99) for map volume, poor-to-excellent (ICC = 0.11-0.86) for map area, and fair-to-excellent for CoG (ICC = 0.25-0.8) across muscles. There was Bayesian evidence of equivalence (BF's > 3) in most map outcomes between rapid and traditional maps across all muscles, supporting the validity of the rapid mapping method. Overall, rapid TMS mapping produced similar estimates of map parameters to the traditional method, however the reliability results were mixed. As mapping of non-upper limb muscles is relatively challenging, rapid mapping is a promising substitute for traditional mapping, however further work is required to refine this method.

Intermittent normobaric hypoxia alters substrate partitioning and muscle oxygenation in individuals with obesity: implications for fat burning.

This single-blind, crossover study aimed to measure and evaluate the short-term metabolic responses to continuous and intermittent hypoxic patterns in individuals with obesity. Indirect calorimetry was used to quantify changes in resting metabolic rate (RMR), carbohydrate (CHOox, %CHO), and fat oxidation (FATox, %FAT) in nine individuals with obesity pre and post: 1) breathing normoxic air [normoxic sham control (NS-control)], 2) breathing continuous hypoxia (CH), or 3) breathing intermittent hypoxia (IH). A mean peripheral oxygen saturation ([Formula: see text]) of 80-85% was achieved over a total of 45 min of hypoxia. Throughout each intervention, pulmonary gas exchanges, oxygen consumption (V̇o2) carbon dioxide production (V̇co2), and deoxyhemoglobin concentration (Δ[HHb]) in the vastus lateralis were measured. Both RMR and CHOox measured pre- and postinterventions were unchanged following each treatment: NS-control, CH, or IH (all P > 0.05). Conversely, a significant increase in FATox was evident between pre- and post-IH (+44%, P = 0.048). Although the mean Δ[HHb] values significantly increased during both IH and CH (P < 0.05), the greatest zenith of Δ[HHb] was achieved in IH compared with CH (P = 0.002). Furthermore, there was a positive correlation between Δ[HHb] and the shift in FATox measured pre- and postintervention. It is suggested that during IH, the increased bouts of muscle hypoxia, revealed by elevated Δ[HHb], coupled with cyclic periods of excess posthypoxia oxygen consumption (EPHOC, inherent to the intermittent pattern) played a significant role in driving the increase in FATox post-IH.

Effect of isometric quadriceps exercise on local microcirculation of the infrapatellar fat pad in female patients with knee osteoarthritis.

OBJECTIVE: To elucidate the local microcirculation of the infrapatellar fat pad (IFP) in patients with knee osteoarthritis (KOA) by determining the changes in IFP hardness and hemoglobin concentration during isometric quadriceps exercise (IQE). DESIGN: In this observational cross-sectional study, patients diagnosed with bilateral KOA were included in the KOA group (30 knees), healthy older adults in the control group (20 knees), and younger adults in the young group (20 knees). Ultrasonography was performed at rest and during IQE to measure IFP hardness based on shear wave velocity. Near-infrared spectroscopy was performed to measure oxygenated hemoglobin (O2Hb), deoxygenated hemoglobin (HHb), and total hemoglobin (cHb) in the IFP before (Baseline), during (IQE task), and after IQE (Post). IFP hardness and O2Hb, HHb, and cHb concentration were analyzed using a linear mixed model for the groups and measurement points. RESULTS: During IQE, IFP hardness changes were significantly less in the KOA group than in the other groups (KOA: 95 % confidence intervals (CIs) [-0.854, 0.028]; control: 95 % CI [-0.941, -0.341]; and young: 95 % CI [-2.305, -1.706]). In the KOA group, O2Hb concentration exhibited no significant changes at Post compared with Baseline; however, significant changes were observed in the other groups (KOA: 95 % CI [-1.176, 0.423]; control: 95 % CI [-1.452, -0.276]; and young: 95 % CI [-4.062, -2.102]). CONCLUSIONS: During IQE, changes in hardness and hemoglobin concentration in the IFP were not significant in the KOA group, suggesting impaired local microcirculation of the IFP.

Thigh muscle composition changes in knee osteoarthritis patients during weight loss: Sex-specific analysis using data from osteoarthritis initiative.

OBJECTIVES: Sex of patients with knee osteoarthritis (KOA) may impact changes in thigh muscle composition during weight loss, the most well-known disease-modifying intervention. We investigated longitudinal sex-based changes in thigh muscle quality during weight loss in participants with KOA. METHODS: Using Osteoarthritis Initiative (OAI) cohort data, we included females and males with baseline radiographic KOA who experienced > 5 % reduction in Body Mass Index (BMI) over four years. Using a previously validated deep-learning algorithm, we measured Magnetic Resonance Imaging (MRI)-derived biomarkers of thigh muscles at baseline and year-4. Outcomes were the intra- and inter-muscular adipose tissue (Intra-MAT and Inter-MAT) and contractile percentage of thigh muscles between females and males. The analysis adjusted for potential confounders, such as demographics, risk factors, BMI change, physical activity, diet, and KOA status. RESULTS: A retrospective selection of available thigh MRIs from KOA participants who also had a 4-year weight loss (>5 % of BMI) yielded a sample comprising 313 thighs (192 females and 121 males). Female and male participants exhibited a comparable degree of weight loss (females: -9.72 ± 4.38, males: -8.83 ± 3.64, P-value=0.060). However, the changes in thigh muscle quality were less beneficial for females compared to males, as shown by a less degree of longitudinal decrease in Intra-MAT (change difference,95 %CI: 783.44 mm2/4-year, 505.70 to 1061.19, P-value<0.001) and longitudinal increase in contractile percentage (change difference,95 %CI: -3.9 %/4-year, -6.5 to -1.4, P-value=0.019). CONCLUSIONS: In participants with KOA and 4-year weight loss, the longitudinal changes in thigh muscle quality were overall beneficial but to a less degree in females compared to males. Further research is warranted to investigate the underlying mechanisms and develop sex-specific interventions to optimize muscle quality during weight loss.

Quadriceps muscle contraction causes medial patellofemoral ligament elongation by intermeshed fibers of vastus medialis oblique muscle.

The first aim of this study was to compare the medial patellofemoral length between contracted and relaxed quadriceps muscle and second to assess the importance of the intermeshed vastus medialis oblique fibers. After a priori power analysis (α = 0.05, power [1-ß] = 0.95), 35 healthy males aged 18-30 were prospectively examined with a 3.0-T magnetic resonance imaging (MRI) scanner in 10-15° of knee flexion. Two axial MRI sequences (25 s each) were made with relaxed and contracted quadriceps. Two blinded, independent raters measured twice medial patellofemoral ligament length (curved line) and attachment-to-attachment length (straight line). Mean medial patellofemoral ligament length and attachment-to-attachment length with relaxed quadriceps was: 65.5 mm (SD = 3.7), 59.7 mm (SD = 3.6), and after contraction, it increased to 68.7 mm (SD = 5.3), 61.2 mm (SD = 4.7); p < 0.01 and <0.001, respectively. Intraclass correlation coefficients for intra- and inter-rater reliabilities ranged from 0.55 (moderate) to 0.97 (excellent). Mean medial patellofemoral ligament length elongation after quadriceps contraction was significantly greater (3.2 mm, SD = 3.9) than mean attachment-to-attachment length elongation (1.6 mm, SD = 2.8); p < 0.001. Contraction of quadriceps muscle causes elongation of the medial patellofemoral ligament to the extent greater than the elongation of distance between its attachments. This confirms that medial patellofemoral ligament elongation after quadriceps contraction results not only from movement of its patellar attachment but also directly from intermeshed vastus medialis oblique fibers pulling medial patellofemoral ligament in a different direction creating a bow-like construct in agreement with the "pull-and-guide mechanism" proposed in the literature.

Oldies, but goldies-preserved morphology and stability of antigenic determinants in decades-old cryosections of human m. vastus lateralis.

Fibre typing by immunohistochemistry on cryosections from human skeletal muscle biopsies is an essential tool in the diagnosis and research of muscular diseases, ageing, and responses to exercise training and disuse. Preserving a good quality in these frozen specimens can be challenging especially if they are stored for longer periods before histological processing, which is often the case in studies with a large number of test subjects and/or repeated sampling separated by multiple years. We demonstrate in this article that both, the morphology and reactivity of epitopes to myosin heavy chain isoforms and dystrophin are well preserved in up to 18-year-stored unfixed and unstained cryosections of human m. vastus lateralis (n = 241). Any variation in staining intensity between samples was unrelated to the age of the biopsy donor or the storage period of the unstained cryosections, and in all cases, the obtained images were appropriate for image analysis, such as the determination of the fibre type composition and the fibre cross-sectional area, and quantitative analysis of muscle capillarisation.

Fatiguing exercise reduces cellular passive Young's modulus in human vastus lateralis muscle.

Previous studies demonstrated that acute fatiguing exercise transiently reduces whole-muscle stiffness, which might contribute to increased risk of injury and impaired contractile performance. We sought to elucidate potential intracellular mechanisms underlying these reductions. To that end, the cellular passive Young's modulus was measured in muscle fibres from healthy, young males and females. Eight volunteers (four male and four female) completed unilateral, repeated maximal voluntary knee extensions until task failure, immediately followed by bilateral percutaneous needle muscle biopsy of the post-fatigued followed by the non-fatigued control vastus lateralis. Muscle samples were processed for mechanical assessment and separately for imaging and phosphoproteomics. Fibres were passively (pCa 8.0) stretched incrementally to 156% of initial sarcomere length to assess Young's modulus, calculated as the slope of the resulting stress-strain curve at short (sarcomere length = 2.4-3.0 µm) and long (sarcomere length = 3.2-3.8 µm) lengths. Titin phosphorylation was assessed by liquid chromatography followed by high-resolution mass spectrometry. The passive modulus was significantly reduced in post-fatigued versus control fibres from male, but not female, participants. Post-fatigued samples showed altered phosphorylation of five serine residues (four located within the elastic region of titin) but did not exhibit altered active tension or sarcomere ultrastructure. Collectively, these results suggest that acute fatigue is sufficient to alter phosphorylation of skeletal titin in multiple locations. We also found reductions in the passive modulus, consistent with prior reports in the literature investigating striated muscle stiffness. These results provide mechanistic insight contributing to the understanding of dynamic regulation of whole-muscle tissue mechanics in vivo. HIGHLIGHTS: What is the central question of this study? Previous studies have shown that skeletal muscle stiffness is reduced following a single bout of fatiguing exercise in whole muscle, but it is not known whether these changes manifest at the cellular level, and their potential mechanisms remain unexplored. What is the main finding and its importance? Fatiguing exercise reduces cellular stiffness in skeletal muscle from males but not females, suggesting that fatigue alters tissue compliance in a sex-dependent manner. The phosphorylation status of titin, a potential mediator of skeletal muscle cellular stiffness, is modified by fatiguing exercise. Previous studies have shown that passive skeletal muscle stiffness is reduced following a single bout of fatiguing exercise. Lower muscle passive stiffness following fatiguing exercise might increase risk for soft-tissue injury; however, the underlying mechanisms of this change are unclear. Our findings show that fatiguing exercise reduces the passive Young's modulus in skeletal muscle cells from males but not females, suggesting that intracellular proteins contribute to reduced muscle stiffness following repeated loading to task failure in a sex-dependent manner. The phosphorylation status of the intracellular protein titin is modified by fatiguing exercise in a way that might contribute to altered muscle stiffness after fatiguing exercise. These results provide important mechanistic insight that might help to explain why biological sex impacts the risk for soft-tissue injury with repeated or high-intensity mechanical loading in athletes and the risk of falls in older adults.