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BACKGROUND: Degeneration of the motoneuron and neuromuscular junction (NMJ) and loss of motor units (MUs) contribute to age-related muscle wasting and weakness associated with sarcopenia. However, these features have not been comprehensively investigated in humans. This study aimed to compare neuromuscular system integrity and function at different stages of sarcopenia, with a particular focus on NMJ stability and MU properties. METHODS: We recruited 42 young individuals (Y) (aged 25.98 ± 4.6 years; 57% females) and 88 older individuals (aged 75.9 ± 4.7 years; 55% females). The older group underwent a sarcopenia screening according to the revised guidelines of the European Working Group on Sarcopenia in Older People 2. In all groups, knee extensor muscle force was evaluated by isometric dynamometry, muscle morphology by ultrasound and MU potential properties by intramuscular electromyography (iEMG). MU number estimate (iMUNE) and blood samples were obtained. Muscle biopsies were collected in a subgroup of 16 Y and 52 older participants. RESULTS: Thirty-nine older individuals were non-sarcopenic (NS), 31 pre-sarcopenic (PS) and 18 sarcopenic (S). A gradual decrease in quadriceps force, cross-sectional area and appendicular lean mass was observed across the different stages of sarcopenia (for all P < 0.0001). Handgrip force and the Short Physical Performance Battery score also showed a diminishing trend. iEMG analyses revealed elevated near fibre segment jitter in NS, PS and S compared with Y (Y vs. NS and S: P < 0.0001; Y vs. PS: P = 0.0169), suggestive of age-related impaired NMJ transmission. Increased C-terminal agrin fragment (P < 0.0001) and altered caveolin 3 protein expression were consistent with age-related NMJ instability in all the older groups. The iMUNE was lower in all older groups (P < 0.0001), confirming age-related loss of MUs. An age-related increase in MU potential complexity was also observed. These observations were accompanied by increased muscle denervation and axonal damage, evinced by the increase in neural cell adhesion molecule-positive fibres (Y vs. NS: P < 0.0001; Y vs. S: P = 0.02) and the increase in serum concentration of neurofilament light chain (P < 0.0001), respectively. Notably, most of these MU and NMJ parameters did not differ when comparing older individuals with or without sarcopenia. CONCLUSIONS: Alterations in MU properties, axonal damage, an altered innervation profile and NMJ instability are prominent features of the ageing of the neuromuscular system. These neuromuscular alterations are accompanied by muscle wasting and weakness; however, they appear to precede clinically diagnosed sarcopenia, as they are already detectable in older NS individuals.

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PURPOSE: to investigate the early consequences of type 1 diabetes (T1D) on the neural strategies of muscle force production. METHODS: motor unit (MU) activity was recorded from the vastus lateralis muscle with High-Density surface Electromyography during isometric knee extension at 20 and 40% of maximum voluntary contraction (MVC) in 8 T1D (4 males, 4 females, 30.5 ± 3.6 years) and 8 matched control (4 males, 4 females, 27.3 ± 5.9 years) participants. Muscle biopsies were also collected from vastus lateralis for fiber type analysis, including myosin heavy chain (MyHC) isoform content via protein and mRNA expression. RESULTS: MVC was comparable between groups as well as MU conduction velocity, action potentials' amplitude and proportions of MyHC protein isoforms. Nonetheless, MU discharge rate, relative derecruitment thresholds and mRNA expression of MyHC isoform I were lower in T1D. CONCLUSIONS: young people with uncomplicated T1D present a different neural control of muscle force production. Furthermore, differences are detectable non-invasively in absence of any functional manifestation (i.e., force production and fiber type distribution). These novel findings suggest that T1D has early consequences on the neuromuscular system and highlights the necessity of a better characterization of neural control in this population.

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BACKGROUND: There has been growing interest in using unstable devices in training protocols. This study aimed to assess the effectiveness of two multimodal exercise interventions (i.e., on stable and unstable surfaces) on dynamic balance control and lower limb strength in older adults. METHODS: Sixty-two older adults were randomly assigned to two intervention groups (N = 20, stable group; N = 19, unstable group), and to a control group (N = 18). In this single-blinded randomized controlled study, the two intervention groups underwent a 12-week training program twice a week for 45 min, consisting of strength and balance exercises. The stable (ST) group performed the training program over stable surfaces, while the unstable (UNST) group over unstable surfaces. Dynamic balance was assessed by computing the center of pressure (CoP) trajectory while a driven movable platform induced an unexpected perturbation of the base of support. Specifically, we considered the following CoP-related parameters within a 2.5-s temporal window from the beginning of the perturbation: displacement (Area95), mean velocity (Unit Path), anterior-posterior first peak (FP), post perturbation variability (PPV), and maximal oscillations (ΔCoPMax). The dominant quadriceps strength was measured through an isometric maximal voluntary contraction on an instrumented chair. RESULTS: Four out of five CoP-related parameters (i.e., Area95, Unit Path, ΔCoPMax, and PPV) significantly improved in the UNST group from a minimum of 14.28% (d = 0.44) to a maximum of 52.82% (d = 0.58). The ST group significantly improved only in two (i.e., ΔCoPMax, and PPV) out of five CoP-related parameters with an enhancement of 12.48% (d = 0.68) and 19.10% (d = 1.06). Both intervention groups increased the maximal isometric quadriceps strength (UNST:17.27%, d = 0.69; ST:22.29%, d = 0.98). The control group did not show changes in any of the parameters considered. CONCLUSIONS: Stable surfaces promoted faster increments of muscular strength. Unstable surfaces were more effective in enhancing dynamic balance efficiency. These findings suggested the employment of multimodal training on unstable rather than stable surfaces to potentially lower the incidence of falls in older adults. TRIAL REGISTRATION: NCT05769361, retrospectively registered 13 March 2023, https://clinicaltrials.gov/study/NCT05769361?lat=45.3661864&lng=11.8209139&locStr=Padova,%20Italy&distance=50&page=11&rank=107 .

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BACKGROUND: Increasing interest surrounds the utility of blood-based biomarkers for diagnosing sarcopenia. C-terminal agrin fragment (CAF), a marker of neuromuscular junction stability, is amongst the most promising candidates; however, a dearth of reference data impedes the incorporation of its use in public health settings. This study aimed to establish reference values for plasma CAF concentrations across adulthood in a large, well-characterized cohort of healthy adults; and comprehensively examine the association between plasma CAF levels and skeletal muscle health. METHODS: One thousand people aged between 18 and 87 years took part in this study (mean age = 50.4 years; 51% females). Body composition and muscle strength were examined using DXA and hand dynamometry. Plasma CAF concentrations were measured, in duplicate, using commercially available ELISA kits. Sarcopenia and individual sarcopenia signatures [low skeletal muscle index (SMI) only/low grip strength only] were classified using the EWGSOP2 algorithm. RESULTS: Detailed reference CAF values, according to sex and age, are presented. A significant but modest age-related increase in plasma CAF concentration was observed (P = 0.018). Across adulthood, CAF concentrations were negatively associated with grip strength and SMI (both P < 0.001). In people ≥50 years old, CAF concentrations were 22.6% higher in those with sarcopenia (P < 0.001), 11.3% higher in those with low SMI (P = 0.006) and 9.6% higher in those with low grip strength (P = 0.0034), compared with controls. People in the highest CAF concentration quartile, had 3.25 greater odds for sarcopenia (95% CI = 1.41-7.49, P = 0.005), 2.76 greater odds for low SMI (95% CI = 1.24-5.22, P = 0.012), and 2.56 greater odds for low grip strength (95% CI = 1.07-5.57, P = 0.037), compared with those in the lowest quartile. People with a CAF Z-score ≥2 had 9.52 greater odds for sarcopenia (95% CI = 3.01-30.05, P < 0.001) compared with a Z-score <1. Plasma CAF concentration had an acceptable level of diagnostic accuracy for sarcopenia (AUC = 0.772, 95% CI = 0.733-0.807, P < 0.001). CONCLUSIONS: The reference values presented herein may guide the clinical interpretation of circulating CAF and help identify people at risk of poor skeletal muscle outcomes for inclusion in therapeutic interventions. Our findings add clarity to existing data, demonstrating a robust relationship between circulating CAF and skeletal muscle integrity in the largest adult cohort to date, and support the use of CAF as an accessible, cost-effective screening tool for sarcopenia. However, further research into the prognostic utility of plasma CAF, and the establishment of normative data from other populations, are urgently needed if routine CAF screening is to be embedded into public healthcare settings.

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PURPOSE: Prior evidence has shown that neural factors contribute to the loss of muscle force after skeletal muscle disuse. However, little is known about the specific neural mechanisms altered by disuse. Persistent inward current (PIC) is an intrinsic property of motoneurons responsible for prolonging and amplifying the synaptic input, proportionally to the level of neuromodulation, thus influencing motoneuron discharge rate and force production. Here, we hypothesized that short-term unilateral lower limb suspension (ULLS) would reduce the neuromodulatory input associated with PIC, contributing to the reduction of force generation capacity. In addition, we tested whether physical exercise would restore the force generation capacity by reestablishing the initial level of neuromodulatory input. METHODS: In 12 young adults, we assessed maximal voluntary contraction pre- and post-10 d of ULLS and after 21 d of active recovery (AR) based on resistance exercise. PIC was estimated from high-density surface electromyograms of the vastus lateralis muscle as the delta frequency (Δ F ) of paired motor units calculated during isometric ramped contractions. RESULTS: The values of Δ F were reduced after 10 d of ULLS (-33%, P < 0.001), but were fully reestablished after the AR (+29.4%, P < 0.001). The changes in estimated PIC values were correlated ( r = 0.63, P = 0.004) with the reduction in maximal voluntary contraction after ULLS (-29%, P = 0.002) and its recovery after the AR (+28.5%, P = 0.003). CONCLUSIONS: Our findings suggest that PIC estimates are reduced by muscle disuse and may contribute to the loss of force production and its recovery with exercise. Overall, this is the first study demonstrating that, in addition to peripheral neuromuscular changes, central neuromodulation is a major contributor to the loss of force generation capacity after disuse, and can be recovered after resistance exercise.

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We aimed to determine whether the anatomical location (intramuscular tendon or T-Junction) of hamstring muscle injuries in professional men's rugby union associates with a prolonged time to return to full training and a higher rate of re-injury/subsequent injury. We reviewed the medical records of an Irish professional rugby union club to identify hamstring muscle injuries incurred across five seasons. Clinicians and players were not blinded to MRI results at the time of rehabilitation. A blinded musculoskeletal radiologist re-classified all included injuries (n = 91) according to the British Athletics Muscle Injury Classification framework. Players who sustained an injury with intramuscular tendon involvement required a longer time to return to full training compared to players who sustained an injury without intramuscular tendon involvement (78 days vs. 24 days). Players who sustained a biceps femoris injury with T-junction involvement did not require a longer time to return to full training compared to players who sustained a biceps femoris injury without T-junction involvement (29 days vs. 27 days). Injuries with either intramuscular tendon or T-junction involvement were not associated with an increased rate of re-injury/subsequent injury to the same limb (intramuscular tendon involvement - odds ratio = 0.96, T-junction involvement - odds ratio = 1.03). When a hamstring muscle injury involves the intramuscular tendon, the injured player and stakeholders should be made aware that a longer time to return to full training is likely required. T-junction involvement does not alter the expected clinical course of biceps femoris injuries.

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Although strong positive correlations exist between grip strength and cardiovascular health, the association between grip strength and blood pressure (BP) is less clear. In this regard, a more precise relationship between grip strength and BP may be revealed by considering adiposity. We examined the association between grip strength and BP in 9424 individuals aged 18-92 years, while controlling for or stratifying by body mass index (BMI) or body fat (BF)%. Grip strength, BP and BF% were determined using dynamometry, sphygmomanometry and dual-energy x-ray absorptiometry. Overall, those with elevated BP had greater grip strength than those with normal BP (39.17 kg vs 38.38 kg, p < 0.001); however, following stratification this was only observed in overweight or obese individuals (42.08 kg vs 41.10 kg, p = 0.003 and 41.34 kg vs 40.03 kg, p = 0.033), and those within the highest BF% tertile (37.95 kg vs 36.52 kg, p < 0.001). Overall, higher grip strength was associated with an increased odds for elevated BP (OR = 1.014, 95% CI = 1.004-1.024, p = 0.004); however, after stratification the increased odds was only observed in overweight or obese individuals (OR = 1.025, 95% CI = 1.010-1.039, p < 0.001 and OR = 1.018, 95% CI = 1.004-1.031, p = 0.010), and those within the highest BF% tertile (OR = 1.036, 95% CI = 1.022-1.051, p < 0.001). Individuals with low grip strength and high BF% had lower odds for elevated BP (OR = 0.514, 95% CI = 0.341-0.775, p = 0.002), whereas those with low grip strength and low BF% had higher odds for elevated BP (OR = 2.162, 95% CI = 1.026-4.555, p = 0.043). Our findings show that higher grip strength is related to higher BP in overweight or obese individuals, or those with a high BF%. Having a BMI < 25 kg/m2 or lower BF% may neutralise this association.

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High-Density surface Electromyography (HD-sEMG) is the most established technique for the non-invasive analysis of single motor unit (MU) activity in humans. It provides the possibility to study the central properties (e.g., discharge rate) of large populations of MUs by analysis of their firing pattern. Additionally, by spike-triggered averaging, peripheral properties such as MUs conduction velocity can be estimated over adjacent regions of the muscles and single MUs can be tracked across different recording sessions. In this tutorial, we guide the reader through the investigation of MUs properties from decomposed HD-sEMG recordings by providing both the theoretical knowledge and practical tools necessary to perform the analyses. The practical application of this tutorial is based on openhdemg, a free and open-source community-based framework for the automated analysis of MUs properties built on Python 3 and composed of different modules for HD-sEMG data handling, visualisation, editing, and analysis. openhdemg is interfaceable with most of the available recording software, equipment or decomposition techniques, and all the built-in functions are easily adaptable to different experimental needs. The framework also includes a graphical user interface which enables users with limited coding skills to perform a robust and reliable analysis of MUs properties without coding.

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PURPOSE: This study aimed to non-invasively test the hypothesis that (a) short-term lower limb unloading would induce changes in the neural control of force production (based on motor units (MUs) properties) in the vastus lateralis muscle and (b) possible changes are reversed by active recovery (AR). METHODS: Ten young males underwent 10 days of unilateral lower limb suspension (ULLS) followed by 21 days of AR. During ULLS, participants walked exclusively on crutches with the dominant leg suspended in a slightly flexed position (15°-20°) and with the contralateral foot raised by an elevated shoe. The AR was based on resistance exercise (leg press and leg extension) and executed at 70% of each participant's 1 repetition maximum, 3 times/week. Maximal voluntary isometric contraction (MVC) of knee extensors and MUs properties of the vastus lateralis muscle were measured at baseline, after ULLS, and after AR. MUs were identified using high-density electromyography during trapezoidal isometric contractions at 10%, 25%, and 50% of the current MVC, and individual MUs were tracked across the 3 data collection points. RESULTS: We identified 1428 unique MUs, and 270 of them (18.9%) were accurately tracked. After ULLS, MVC decreased by 29.77%, MUs absolute recruitment/derecruitment thresholds were reduced at all contraction intensities (with changes between the 2 variables strongly correlated), while discharge rate was reduced at 10% and 25% but not at 50% MVC. Impaired MVC and MUs properties fully recovered to baseline levels after AR. Similar changes were observed in the pool of total as well as tracked MUs. CONCLUSION: Our novel results demonstrate, non-invasively, that 10 days of ULLS affected neural control predominantly by altering the discharge rate of lower-threshold but not of higher-threshold MUs, suggesting a preferential impact of disuse on motoneurons with a lower depolarization threshold. However, after 21 days of AR, the impaired MUs properties were fully restored to baseline levels, highlighting the plasticity of the components involved in neural control.

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Diabetes mellitus represents a group of physiological dysfunctions characterized by hyperglycaemia resulting directly from insulin resistance (in the case of type 2 diabetes mellitus-T2DM), inadequate insulin secretion/production, or excessive glucagon secretion (in type 1 diabetes mellitus-T1DM) [...].

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BACKGROUND: Although handgrip strength (HGS) asymmetry has clinical screening utility, its relevance to sarcopenia is unknown. This study examined the relationship between HGS asymmetry and sarcopenia signatures, and explored the relevance of circulating neural/neuromuscular markers. METHODS: 9403 individuals aged 18-92 years participated in this study. Maximal HGS and skeletal muscle index (SMI) were determined using hand dynamometry and DXA. Sarcopenia was diagnosed upon the presence of low HGS and low SMI, according to cohort-specific thresholds. Plasma biomarkers were measured by ELISA in a sub-group of 269 participants aged 50-83 years. Asymmetry was determined as the highest recorded HGS divided by the highest recorded HGS of the opposite hand. Individuals with a ratio > 1.10 were classified as having asymmetrical HGS. RESULTS: Subjects with asymmetrical HGS had significantly lower SMI (7.67 kg/m2 vs 7.71 kg/m2, p = 0.004) and lower HGS (37.82 kg vs 38.91 kg, p < 0.001) than those with symmetrical HGS. In those aged ≥ 50 years asymmetrical HGS was associated with 2.67 higher odds for sarcopenia [95% confidence interval: (CI) = 1.557-4.561, p < 0.001], 1.83 higher odds for low HGS only (CI 1.427-2.342, p < 0.001), and 1.79 higher odds for low SMI only (CI 1.257-2.554, p = 0.001). HGS asymmetry demonstrated acceptable diagnostic accuracy for sarcopenia (AUC = 0.727, CI 0.658-0.796, p < 0.001). Plasma neural cell adhesion molecule concentrations were 19.6% higher in individuals with asymmetrical HGS (185.40 ng/mL vs 155.00 ng/mL, p < 0.001) than those with symmetrical HGS. DISCUSSION: Our findings demonstrate the utility of HGS asymmetry as a screening tool that may complement existing strategies seeking to combat sarcopenia. Biomarker analyses suggest that heightened denervation may be an important aetiological factor underpinning HGS asymmetry.

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Hamstring strain injuries (HSI) are one of the most common sport-related injuries. They have a high injury burden and a high recurrence rate. The development of novel muscle injury grading systems has provided new insights into the possible impact of injury location on the time to return to play (TTRTP) and re-injury following HSI. In particular, injuries to the intramuscular tendon (IMT) may be present in up to 41% of all HSI and have been described as a 'serious thigh muscle strain'. Re-injury rates as high as 60% have been described in elite track and field athletes, as well as prolonged TTRTP. A systematic search was carried out using appropriate keywords to identify articles reporting on HSI involving the IMT in athletes. The primary aim was to determine whether IMT injuries warrant being classified as a distinct clinical entity with different expected outcomes to other hamstring muscle injuries. This narrative review summarises the existing evidence on: (1) the anatomy of the IMT and its response to injury; (2) the role of MRI and novel grading scales in IMT injury management (3) clinical assessment of IMT injuries, (4) TTRTP and re-injury rates across sports following IMT, (5) conservative rehabilitation and the role of specific 'IMT-oriented' strategies, and (6) indications for and approaches to surgery. The review found that important clinical outcomes such as re-injury rates and TTRTP vary across populations, cohorts and sports which suggest that outcomes are specific to the sporting context. Bespoke rehabilitation, tailored to IMT injury, has been shown to significantly reduce re-injuries in elite track and field athletes, without compromising TTRTP. Continued prospective studies across other sports and cohorts, are warranted to further establish relevant clinical findings, indications for surgical intervention and outcomes across other sporting cohorts.

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Being overweight is already considered a metabolic risk factor, which can be overcome by increasing cardiorespiratory fitness (CRF). Acute exercise is known to induce changes in plasma hormones and heat shock proteins release. However, there is a lack of studies investigating the impact of body composition and CRF on these variables following acute aerobic exercise. To assess the influence of body composition and cardiorespiratory fitness on plasma heat shock protein 72 kDa (HSP72), norepinephrine (NE), insulin, and glucose responses to an acute aerobic exercise bout in the fed state. Twenty-four healthy male adults were recruited and allocated into three groups: overweight sedentary (n = 8), normal weight sedentary (n = 8), and normal weight active (n = 8). The volunteers performed an acute moderate exercise session on a treadmill at 70% of VO2 peak. Blood samples were drawn at baseline, immediately post-exercise, and at 1-h post-exercise. The exercise session did not induce changes in HSP72 nor NE but changes in glucose and insulin were affected by body mass index. Also, subjects with elevated CRF maintain reduced NE through exercise. At baseline, the overweight sedentary group showed elevated NE, insulin, and glucose; these last two impacting the HOMA-IR index. Thirty minutes of aerobic exercise at 70% VO2 peak, in the fed state, did not change the levels of plasma NE and HSP72. Elevated body composition seems to impact metabolic profile and increase sympathetic activity. Conversely, subjects with increased cardiorespiratory fitness seem to have attenuated sympathetic activity.

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Zebrafish has become an essential model organism in modern biomedical research. Owing to its distinctive features and high grade of genomic homology with humans, it is increasingly employed to model diverse neurological disorders, both through genetic and pharmacological intervention. The use of this vertebrate model has recently enhanced research efforts, both in the optical technology and in the bioengineering fields, aiming at developing novel tools for high spatiotemporal resolution imaging. Indeed, the ever-increasing use of imaging methods, often combined with fluorescent reporters or tags, enable a unique chance for translational neuroscience research at different levels, ranging from behavior (whole-organism) to functional aspects (whole-brain) and down to structural features (cellular and subcellular). In this work, we present a review of the imaging approaches employed to investigate pathophysiological mechanisms underlying functional, structural, and behavioral alterations of human neurological diseases modeled in zebrafish.

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Human skeletal muscle atrophy and a disproportionate force loss occur within a few days of unloading in space and on Earth, but the underlying mechanisms are not fully understood. Disruption of neuromuscular junction homeostasis has been proposed as one of the possible causes. Here, we investigated the potential mechanisms involved in this neuromuscular disruption induced by a 10-day unilateral lower limb suspension (ULLS) in humans. Specifically, we investigated hemichannels' upregulation, neuromuscular junction and axonal damage, neurotrophins' receptor downregulation and inflammatory transcriptional signatures. Biomarkers were evaluated at local and systemic levels. At the sarcolemmal level, changes were found to be associated with an increased expression of connexin 43 and pannexin-1. Upregulation of the inflammatory transcripts revealed by deep transcriptomics was found after 10 days of ULLS. The destabilisation of the neuromuscular junction was not accompanied by changes in the secretion of the brain-derived neurotrophic factor and neurotrophin-4, while their receptor, BDNF/NT growth factors receptor (TrkB), decreased. Furthermore, at 5 days of ULLS, there was already a significant upregulation of the serum neurofilament light chain concentration, an established clinical biomarker of axonal injury. At 10 days of ULLS, other biomarkers of early denervation processes appeared. Hence, short periods of muscle unloading induce sarcolemmal hemichannels upregulation, inflammatory transcripts upregulation, neuromuscular junction instability and axonal damage.

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Purpose: To determine whether differences exist in the architectural characteristics of the hamstring muscles of elite-level male and female rugby union players. Methods: Forty elite-level rugby union players (male n = 20, female n = 20) participated in this cross-sectional study. A sonographer acquired static ultrasound images using a 92 mm linear transducer to quantify (via a semi-automated tracing software tool) the architectural characteristics (muscle length, fascicle length, pennation angle, and muscle thickness) of the biceps femoris long head and semimembranosus muscles of participants' left limb. Muscle length and muscle thickness of the biceps femoris short head and semitendinosus muscles of participants' left limb were also quantified. Bonferroni adjusted independent samples t-tests were performed to evaluate whether differences exist in the architectural characteristics of the hamstring muscles of elite-level male and female rugby union players. Results: There were no significant differences in fascicle length or pennation angle of the hamstring muscles of elite-level male and female rugby union players. Some significant differences in muscle thickness (biceps femoris short head, and semimembranosus) and muscle length (biceps femoris short head, biceps femoris long head, semitendinosus, and semimembranosus) were observed; in all cases the male players had thicker and longer muscles. Conclusion: At a group level, hamstring muscle fascicle length and pennation angle are unlikely to be a sex-specific intrinsic risk factor for Hamstring strain injuries.

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Although physiological data suggest that neuromuscular junction (NMJ) dysfunction is a principal mechanism underpinning sarcopenia, genetic studies have implicated few genes involved in NMJ function. Accordingly, we explored whether genes encoding agrin (AGRN) and neurotrypsin (PRSS12) were associated with sarcopenia phenotypes: muscle mass, strength and plasma C-terminal agrin fragment (CAF). PhenoScanner was used to determine if AGRN and/or PRSS12 variants had previously been implicated with sarcopenia phenotypes. For replication, we combined genotype from whole genome sequencing with phenotypic data from 6715 GenoFit participants aged 18-83 years. Dual energy X-ray absorptiometry assessed whole body lean mass (WBLM) and appendicular lean mass (ALM), hand dynamometry determined grip strength and ELISA measured plasma CAF in a subgroup (n = 260). Follow-up analyses included eQTL analyses, carrier analyses, single-variant and gene-burden tests. rs2710873 (AGRN) and rs71608359 (PRSS12) associate with muscle mass and strength phenotypes, respectively, in the UKBB (p = 8.9 × 10-6 and p = 8.4 × 10-6) and GenoFit cohort (p = 0.019 and p = 0.014). rs2710873 and rs71608359 are eQTLs for AGRN and PRSS12, respectively, in ≥ three tissues. Compared to non-carriers, carriers of rs2710873 had 4.0% higher WBLM and ALM (both p < 0.001), and 9.5% lower CAF concentrations (p < 0.001), while carriers of rs71608359 had 2.3% lower grip strength (p = 0.034). AGRN and PRSS12 are associated with muscle strength and mass in single-variant analyses, while PRSS12 has further associations with muscle strength in gene-burden tests. Our findings provide novel evidence of the relevance of AGRN and PRSS12 to sarcopenia phenotypes and support existing physiological data illustrating the importance of the NMJ in maintaining muscle health during ageing.

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In rodent motor cortex, the rostral forelimb area (RFA) and the caudal forelimb area (CFA) are major actors in orchestrating the control of complex forelimb movements. However, their intrinsic connectivity and reciprocal functional organization are still unclear, limiting our understanding of how the brain coordinates and executes voluntary movements. Here, we causally probe cortical connectivity and activation patterns triggered by transcranial optogenetic stimulation of ethologically relevant complex movements exploiting a large-scale all-optical method in awake mice. Results show specific activation features for each movement class, providing evidence for a segregated functional organization of CFA and RFA. Importantly, we identify a second discrete lateral grasping representation area, namely the lateral forelimb area (LFA), with unique connectivity and activation patterns. Therefore, we propose the LFA as a distinct forelimb representation in the mouse somatotopic motor map.

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PURPOSE: To assess the intra-rater reliability of static wide field of view ultrasound to quantify the architectural characteristics of the hamstring muscles. METHODS: Twenty amateur male athletes were recruited. Their left hamstring muscles were assessed using static wide field of view ultrasound on two separate occasions. Static ultrasound images were acquired by a single sonographer using a 92mm linear transducer. The architectural characteristics (muscle length, fascicle length, pennation angle and muscle thickness) from two distinct locations of the bicep femoris long head and semimembranosus were evaluated. Muscle length and thickness of the bicep femoris short head and semitendinosus muscle were also evaluated. Intraclass correlation coefficient analyses were performed to determine the intra-rater reliability of the performed measurements. RESULTS: Both muscle (intraclass correlation coefficient = 0.99; standard error of measurement = 4.3 to 6.6mm) and fascicle (intraclass correlation coefficient = 0.92 to 0.98; standard error measurement = 1.1 to 2.4mm) length were measured with excellent intra-rater reliability. Muscle thickness was measured with excellent reliability (intraclass correlation coefficient = 0.9 to 0.96; standard error of measurement = 0.91mm to 1.4mm) for all hamstring muscles except for the proximal segments of the bicep femoris short head (intraclass correlation coefficient = 0.85; standard error of measurement = 0.84mm) and semitendinosus (intraclass correlation coefficient = 0.88; standard error of measurement = 0.82mm), which were measured with good reliability. Pennation angle was measured with good reliability (intraclass correlation coefficient = 0.77 to 0.87; standard error of measurement = 1 to 1.6°). CONCLUSION: The architectural characteristics of the hamstring muscles of male amateur athletes can be reliably quantified using static wide field of view ultrasound.

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Electrophysiological alterations of the neuromuscular junction (NMJ) and motor unit potential (MUP) with unloading are poorly studied. We aimed to investigate these aspects and the underlying molecular mechanisms with short-term unloading and active recovery (AR). Eleven healthy males underwent a 10-day unilateral lower limb suspension (ULLS) period, followed by 21-day AR based on resistance exercise. Quadriceps femoris (QF) cross-sectional area (CSA) and isometric maximum voluntary contraction (MVC) were evaluated. Intramuscular electromyographic recordings were obtained during 10% and 25% MVC isometric contractions from the vastus lateralis (VL). Biomarkers of NMJ molecular instability (serum c-terminal agrin fragment, CAF), axonal damage (neurofilament light chain) and denervation status were assessed from blood samples and VL biopsies. NMJ and ion channel transcriptomic profiles were investigated by RNA-sequencing. QF CSA and MVC decreased with ULLS. Increased CAF and altered NMJ transcriptome with unloading suggested the emergence of NMJ molecular instability, which was not associated with impaired NMJ transmission stability. Instead, increased MUP complexity and decreased motor unit firing rates were found after ULLS. Downregulation of ion channel gene expression was found together with increased neurofilament light chain concentration and partial denervation. The AR period restored most of these neuromuscular alterations. In conclusion, the human NMJ is destabilized at the molecular level but shows functional resilience to a 10-day unloading period at least at relatively low contraction intensities. However, MUP properties are altered by ULLS, possibly due to alterations in ion channel dynamics and initial axonal damage and denervation. These changes are fully reversed by 21 days of AR. KEY POINTS: We used integrative electrophysiological and molecular approaches to comprehensively investigate changes in neuromuscular integrity and function after a 10-day unilateral lower limb suspension (ULLS), followed by 21 days of active recovery in young healthy men, with a particular focus on neuromuscular junction (NMJ) and motor unit potential (MUP) properties alterations. After 10-day ULLS, we found significant NMJ molecular alterations in the absence of NMJ transmission stability impairment. These findings suggest that the human NMJ is functionally resilient against insults and stresses induced by short-term disuse at least at relatively low contraction intensities, at which low-threshold, slow-type motor units are recruited. Intramuscular electromyography analysis revealed that unloading caused increased MUP complexity and decreased motor unit firing rates, and these alterations could be related to the observed changes in skeletal muscle ion channel pool and initial and partial signs of fibre denervation and axonal damage. The active recovery period restored these neuromuscular changes.

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