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Non-adrenergic prostate smooth muscle contractions may account for the limited effectiveness of α 1 -adrenoceptor antagonists, which are the first-line option for medical treatment of voiding symptoms suggestive of benign prostatic hyperplasia. In non-human prostates, purinergic agonists induce contractions reaching similar magnitudes as α 1 -adrenergic contractions. However, evidence for the human prostate is highly limited, and pointed to much weaker purinergic contractions. Here, we examined contractions of different purinergic agonists in human prostate tissues. Tissues were obtained from radical prostatectomy. Contractions were studied in an organ bath, and expression of purinergic receptors was studied by RT-PCR. Electric field stimulation (EFS)–induced contractions amounted to 104% of KCl-induced contractions (95% CI: 84–124%). From all tested agonists, only ATP induced concentration-dependent contractions, reaching an average maximum of 18% (12–24%) of KCl. Maximum tensions following application of other agonists averaged to 7.1% of KCl for α,β-methylene-ATP (1.8–12.4%), 3.9% for β,γ-methylene-ATP (2.0–5.4%), 3.1% for 2-methylthio-ATP (− 0.1–6.3%), and 5.1% for ATPγS (1.0–9.2%). Responses were not affected by the P2X antagonist NF023 or the P2Y antagonist PPADS. mRNA expression of P2X1-4 correlated with expression of a marker for catecholaminergic nerves, although neither ATP, NF023, nor PPADS changed EFS-induced contractions. Correlation between expression of receptors and the smooth muscle marker calponin was not observed. Our findings point to a low relevance of purinergic contractions in the human prostate, compared to other contractile stimuli in the human prostate and compared to purinergic contractions in non-human prostates. Purinergic contractions in the human prostate are not sensitive to NF023 or PPADS.

Neuromodulation plays a central role in human movement control. An imbalance of neurotransmitters, especially dopamine and serotonin, can be associated with various neurological disorders causing tremors or spasms. Specifically, serotonin was shown to scale motoneuron excitability following intense muscle contractions, affecting short-latency reflexes. Likely, it may also influence motoneuron modulation in prolonged contractions, although this lacks experimental evidence. An intriguing test case for this hypothesis is presented by the Kohnstamm phenomenon, where sustained muscle contractions lead to prolonged amplified EMG activity and involuntary motions, aligning with the timescale of serotonergic amplification. The suspected serotonin influence on this effect was tested in a placebo-controlled human user study with 14 participants, where half were administered the serotonin antagonist Cyproheptadine and the other half a placebo. Comparing EMG and force responses after inducing the Kohnstamm phenomenon in the deltoid muscles revealed statistically significant faster EMG decay with the serotonin antagonist, while decay remained consistent in the placebo group compared to the response of the same participant group without medication. The force measurements showed the same trend, although no significance. This provides new data-based evidence that serotonin contributes to long-term motoneuron modulation, extending previous findings about the dedicated role and influence of this neurotransmitter. Additionally, the work suggests the phenomenon as an interesting test case to investigate the dedicated involvement of different neurocontrol mechanisms such as Persistent Inward Currents.

Loss of mitochondrial function contributes to fatigue, exercise intolerance and muscle weakness, and is a key factor in the disability that develops with age and a wide variety of chronic disorders. Here, we describe the impact of a first-in-class cardiolipin-binding compound that is targeted to mitochondria and improves oxidative phosphorylation capacity (Elamipretide, ELAM) in a randomized, double-blind, placebo-controlled clinical trial. Non-invasive magnetic resonance and optical spectroscopy provided measures of mitochondrial capacity (ATPmax) with exercise and mitochondrial coupling (ATP supply per O2 uptake; P/O) at rest. The first dorsal interosseous (FDI) muscle was studied in 39 healthy older adult subjects (60 to 85 yrs of age; 46% female) who were enrolled based on the presence of poorly functioning mitochondria. We measured volitional fatigue resistance by force-time integral over repetitive muscle contractions. A single ELAM dose elevated mitochondrial energetic capacity in vivo relative to placebo (ΔATPmax; P = 0.055, %ΔATPmax; P = 0.045) immediately after a 2-hour infusion. No difference was found on day 7 after treatment, which is consistent with the half-life of ELAM in human blood. No significant changes were found in resting muscle mitochondrial coupling. Despite the increase in ATPmax there was no significant effect of treatment on fatigue resistance in the FDI. These results highlight that ELAM rapidly and reversibly elevates mitochondrial capacity after a single dose. This response represents the first demonstration of a pharmacological intervention that can reverse mitochondrial dysfunction in vivo immediately after treatment in aging human muscle.

Abstract Context The early events regulating the remodeling program following skeletal muscle damage are poorly understood. Objective The objective of this study was to determine the association between myofibrillar protein synthesis (myoPS) and nuclear factor-kappa B (NF-κB) signaling by nutritionally accelerating the recovery of muscle function following damage. Design, Setting, Participants, and Interventions Healthy males and females consumed daily postexercise and prebed protein-polyphenol (PP; n = 9; 4 females) or isocaloric maltodextrin placebo (PLA; n = 9; 3 females) drinks (parallel design) 6 days before and 3 days after 300 unilateral eccentric contractions of the quadriceps during complete dietary control. Main Outcome Measures Muscle function was assessed daily, and skeletal muscle biopsies were taken after 24, 27, and 36 hours for measurements of myoPS rates using deuterated water, and gene ontology and NF-κB signaling analysis using a quantitative reverse transcription PCR (RT-qPCR) gene array. Results Eccentric contractions impaired muscle function for 48 hours in PLA intervention, but just for 24 hours in PP intervention (P = 0.047). Eccentric quadricep contractions increased myoPS compared with the control leg during postexercise (24–27 hours; 0.14 ± 0.01 vs 0.11 ± 0.01%·h-1, respectively; P = 0.075) and overnight periods (27–36 hours; 0.10 ± 0.01 vs 0.07 ± 0.01%·h-1, respectively; P = 0.020), but was not further increased by PP drinks (P > 0.05). Protein-polyphenol drinks decreased postexercise and overnight muscle IL1R1 (PLA = 2.8 ± 0.4, PP = 1.1 ± 0.4 and PLA = 1.9 ± 0.4, PP = 0.3 ± 0.4 log2 fold-change, respectively) and IL1RL1 (PLA = 4.9 ± 0.7, PP = 1.6 ± 0.8 and PLA = 3.7 ± 0.6, PP = 0.7 ± 0.7 log2 fold-change, respectively) messenger RNA expression (P < 0.05) and downstream NF-κB signaling compared with PLA. Conclusion Protein-polyphenol drink ingestion likely accelerates recovery of muscle function by attenuating inflammatory NF-κB transcriptional signaling, possibly to reduce aberrant tissue degradation rather than increase myoPS rates.

Purpose Dietary nitrate (NO 3 − ) supplementation enhances muscle blood flow and metabolic efficiency in hypoxia, however, its efficacy on neuromuscular function and specifically, the effect on motor unit (MU) activity is less clear. We investigated whether NO 3 − supplementation affected MU activity following a 3 min sustained ischemic contraction and whether this is influenced by blood flow restriction (BFR) during the recovery period. Method In a randomized, double-blinded, cross-over design, 14 males (mean ± SD, 25 ± 6 years) completed two trials following 5 days of supplementation with NO 3 − -rich (NIT) or NO 3 − -depleted (PLA) beetroot juice to modify plasma nitrite (NO 2 − ) concentration (482 ± 92 vs. 198 ± 48 nmol·L −1 , p  < 0.001). Intramuscular electromyography was used to assess MU potential (MUP) size (duration and area) and mean firing rates (MUFR) during a 3 min submaximal (25% MVC) isometric contraction with BFR. These variables were also assessed during a 90 s recovery period with the first half completed with, and the second half completed without, BFR. Results The change in MUP area and MUFR, did not differ between conditions (all p > 0.05), but NIT elicited a reduction in MUP recovery time during brief isometric contractions ( p  < 0.001), and during recoveries with ( p  = 0.002) and without ( p  = 0.012) BFR. Conclusion These novel observations improve understanding of the effects of NO 3 − on the recovery of neuromuscular function post-exercise and might have implications for recovery of muscle contractile function. Trial registration The study was registered on clinicaltrials.gov with ID of NCT05993715 on August 08, 2023.

Background: this study examined the effects of caffeine supplementation on anaerobic performance, neuromuscular efficiency and upper and lower extremities fatigue in Olympic-level boxers. Methods: Eight male athletes, members of the Spanish National Olympic Team, were enrolled in the study. In a randomized double-blind, placebo-controlled, counterbalanced, crossover design, the athletes completed 2 test sessions after the intake of caffeine (6 mg·kg−1) or placebo. Sessions involved initial measures of lactate, handgrip and countermovement jump (CMJ) performance, followed by a 30-seconds Wingate test, and then final measures of the previous variables. During the sessions, electromiography (EMG) data were recorded on the gluteus maximus, biceps femoris, vastus lateralis, gastrocnemius lateral head and tibialis anterior. Results: caffeine enhanced peak power (6.27%, p < 0.01; Effect Size (ES) = 1.26), mean power (5.21%; p < 0.01; ES = 1.29) and reduced the time needed to reach peak power (−9.91%, p < 0.01; ES = 0.58) in the Wingate test, improved jump height in the CMJ (+2.4 cm, p < 0.01), and improved neuromuscular efficiency at peak power in the vastus lateralis (ES = 1.01) and gluteus maximus (ES = 0.89), and mean power in the vastus lateralis (ES = 0.95) and tibialis anterior (ES = 0.83). Conclusions: in these Olympic-level boxers, caffeine supplementation improved anaerobic performance without affecting EMG activity and fatigue levels in the lower limbs. Further benefits observed were enhanced neuromuscular efficiency in some muscles and improved reaction speed.

To determine whether the ergogenic effects of caffeine ingestion on neuromuscular performance are similar when ingestion takes place in the morning and in the afternoon. Double blind, cross-over, randomized, placebo controlled design. Thirteen resistance-trained males carried out bench press and full squat exercises against four incremental loads (25%, 50%, 75% and 90% 1RM), at maximal velocity. Trials took place 60min after ingesting either 6mgkg−1 of caffeine or placebo. Two trials took place in the morning (AMPLAC and AMCAFF) and two in the afternoon (PMPLAC and PMCAFF), all separated by 36–48h. Tympanic temperature, plasma caffeine concentration and side-effects were measured. Plasma caffeine increased similarly during AMCAFF and PMCAFF. Tympanic temperature was lower in the mornings without caffeine effects (36.7±0.4 vs. 37.0±0.5°C for AM vs. PM; p<0.05). AMCAFF increased propulsive velocity above AMPLAC to levels similar to those found in the PM trials for the 25%, 50%, 75% 1RM loads in the SQ exercise (5.4–8.1%; p<0.05). However, in the PM trials, caffeine ingestion did not improve propulsive velocity at any load during BP or SQ. The negative side effects of caffeine were more prevalent in the afternoon trials (13 vs. 26%). The ingestion of a moderate dose of caffeine counteracts the muscle contraction velocity declines observed in the morning against a wide range of loads. Caffeine effects are more evident in the lower body musculature. Evening caffeine ingestion not only has little effect on neuromuscular performance, but increases the rate of negative side-effects reported.

Abstract Background and Objective Studies in humans and mice have demonstrated that the gut hormone glucagon-like peptide 2 (GLP-2) promotes gallbladder relaxation and refilling. Here, we assessed the effect of exogenous GLP-2 on gallbladder motility in the fasted state of healthy men with and without infusion of the potent gallbladder-contracting hormone cholecystokinin (CCK). Methods In a randomized, double-blind, placebo-controlled, crossover study, 15 male participants (mean [SD]: age 24.7 [3.6] years; body mass index 22.9 [1.6] kg/m2) underwent 4 experimental days receiving 2 infusions on each day: either CCK (0.4 pmol × kg−1 × min−1, time 0-180 minutes) + GLP-2 (10 pmol × kg−1 × min−1, time 30-240 minutes), CCK + placebo, placebo + GLP-2, or placebo + placebo, respectively. Gallbladder volume was measured at baseline and throughout the 4-hour study day using ultrasonography. Results Compared to placebo + placebo, GLP-2 + placebo did not affect gallbladder volume, but when infused in combination with CCK, GLP-2 completely abolished the strong gallbladder-contracting effect seen during CCK + placebo infusion, restoring baseline levels of gallbladder volume. Conclusion Exogenous GLP-2 counteracts exogenous CCK-induced gallbladder emptying in healthy men, pointing to a possible therapeutic potential for GLP-2 as a relaxing modulator of gallbladder smooth muscle tone (eg, as a bridge to surgery in biliary colic). The effect may also explain the gallbladder-related adverse events reported for GLP-2 receptor agonists used in the treatment of short bowel syndrome. Clinical Trial Registration number NCT04651868

The aim of the present study was to investigate the acute effect of caffeine or quercetin ingestion on motor unit firing patterns and muscle contractile properties before and after resistance exercise. High-density surface electromyography (HDs-EMG) during submaximal contractions and electrically elicited torque in knee extensor muscles were measured before (PRE) and 60 min after (POST1) ingestion of caffeine, quercetin glycosides, or placebo, and after resistance exercise (POST2) in ten young males. The Convolution Kernel Compensation technique was used to identify individual motor units of the vastus lateralis muscle for the recorded HDs-EMG. Ingestion of caffeine or quercetin induced significantly greater decreases in recruitment thresholds (RTs) from PRE to POST1 compared with placebo (placebo: 94.8 ± 9.7%, caffeine: 84.5 ± 16.2%, quercetin: 91.9 ± 36.7%), and there were significant negative correlations between the change in RTs (POST1-PRE) and RT at PRE for caffeine (rs = − 0.448, p < 0.001) and quercetin (rs =  − 0.415, p = 0.003), but not placebo (rs =  − 0.109, p = 0.440). Significant positive correlations between the change in firing rates (POST2-POST1) and RT at PRE were noted with placebo (rs = 0.380, p = 0.005) and quercetin (rs = 0.382, p = 0.007), but not caffeine (rs = 0.069, p = 0.606). No significant differences were observed in electrically elicited torque among the three conditions. These results suggest that caffeine or quercetin ingestion alters motor unit firing patterns after resistance exercise in different threshold-dependent manners in males.

Background/Objectives: In this study, we aimed to examine the effect of creatine monohydrate (CrM) supplementation on recovery from eccentric exercise-induced muscle damage (EIMD) in diverse populations, including different sexes and age groups. EIMD decreases maximal voluntary contraction (MVC), restricts the range of motion (ROM), and increases muscle stiffness and delayed-onset muscle soreness, all of which negatively impact athletic performance. Therefore, developing effective recovery strategies is essential. Methods: A double-blind, randomized, placebo-controlled trial was conducted with 40 healthy male and female participants. After 33 days of supplementation with either CrM or placebo (crystalline cellulose), the participants performed eccentric exercises. Recovery indices, including MVC, muscle stiffness, subjective muscle extensive soreness, fatigue, and upper arm circumference, were measured at baseline, immediately after exercise, 48 h post-exercise, and 96 h post-exercise. Results: The creatine supplementation group (CRE) demonstrated a significantly quicker recovery of MVC than the placebo group (PLA). Furthermore, reductions in shear modulus and muscle fatigue were observed in the CRE group. Notably, females in the CRE group exhibited a significant suppression of post-exercise edema, suggesting a sex-specific response. Conclusions: These findings indicate that CrM supplementation may enhance recovery from EIMD, contributing to the maintenance of muscle function and the reduction of discomfort after exercise. CrM has the potential to serve as a practical nutritional strategy to promote recovery, not only for athletes, but also for a broader population.