Muscle Function Research Articles

Muscle Organoid and Assembloid Systems.

Skeletal muscle is one of the most complex and largest tissues that perform important processes in the body, including performing voluntary movements and maintaining body temperature. Disruption of muscle homeostasis results in the development of several disorders, including diabetes and sarcopenia. To study the developmental and regenerative dynamics of skeletal muscle and the mechanism behind muscle diseases, it is important to model skeletal muscle and diseases in vitro. Since skeletal muscle has a complex structure and interaction with other tissues and cells that are required to perform their function, conventional 2D cultures are not sufficient to model the skeletal muscle with their interactions. Advances in the field of organoids and assembloids will enable the establishment of more complex and realistic tissue or disease models which cannot be fully recapitulated in conventional 2D culture systems for use in several areas, including disease research, regenerative, and tissue biology. To overcome these limitations, 3D organoid systems and assembloid systems are promising because of their success in recapitulating the complex structural organization, function, and cellular interactions of skeletal muscle.

Estimation of joint torque in dynamic activities using wearable A-mode ultrasound

The human body constantly experiences mechanical loading. However, quantifying internal loads within the musculoskeletal system remains challenging, especially during unconstrained dynamic activities. Conventional measures are constrained to laboratory settings, and existing wearable approaches lack muscle specificity or validation during dynamic movement. Here, we present a strategy for estimating corresponding joint torque from muscles with different architectures during various dynamic activities using wearable A-mode ultrasound. We first introduce a method to track changes in muscle thickness using single-element ultrasonic transducers. We then estimate elbow and knee torque with errors less than 7.6% and coefficients of determination (R2) greater than 0.92 during controlled isokinetic contractions. Finally, we demonstrate wearable joint torque estimation during dynamic real-world tasks, including weightlifting, cycling, and both treadmill and outdoor locomotion. The capability to assess joint torque during unconstrained real-world activities can provide new insights into muscle function and movement biomechanics, with potential applications in injury prevention and rehabilitation.

Treadmill running and mechanical overloading improved the strength of the plantaris muscle in the dystrophin-desmin double knockout (DKO) mouse.

Limited knowledge exists regarding the chronic effect of muscular exercise on muscle function in a murine model of severe Duchenne muscular dystrophy (DMD). Here we determined the effects of 1month of voluntary wheel running (WR), 1month of enforced treadmill running (TR) and 1month of mechanical overloading resulting from the removal of the synergic muscles (OVL) in mice lacking both dystrophin and desmin (DKO). Additionally, we examined the effect of activin receptor administration (AR). DKO mice, displaying severe muscle weakness, atrophy and greater susceptibility to contraction-induced functional loss, were exercised or treated with AR at 1month of age and in situ force production of lower leg muscle was measured at the age of 2months. We found that TR and OVL increased absolute maximal force and the rate of force development of the plantaris muscle in DKO mice. In contrast, those of the tibialis anterior (TA) muscle remained unaffected by TR and WR. Furthermore, the effects of TR and OVL on plantaris muscle function in DKO mice closely resembled those in mdx mice, a less severe murine DMD model. AR also improved absolute maximal force and the rate of force development of the TA muscle in DKO mice. In conclusion, exercise training improved plantaris muscle weakness in severely affected dystrophic mice. Consequently, these preclinical results may contribute to fostering further investigations aimed at assessing the potential benefits of exercise for DMD patients, particularly resistance training involving a low number of intense muscle contractions. KEY POINTS: Very little is known about the effects of exercise training in a murine model of severe Duchenne muscular dystrophy (DMD). One reason is that it is feared that chronic muscular exercise, particularly that involving intense muscle contractions, could exacerbate the disease. In DKO mice lacking both dystrophin and desmin, characterized by severe lower leg muscle weakness, atrophy and fragility in comparison to the less severe DMD mdx model, we found that enforced treadmill running improved absolute maximal force of the plantaris muscle, while that of tibialis anterior muscle remained unaffected by both enforced treadmill and voluntary wheel running. Furthermore, mechanical overloading, a non-physiological model of chronic resistance exercise, reversed plantaris muscle weakness. Consequently, our findings may have the potential to alleviate concerns and pave the way for exploring the prescription of endurance and resistance training as a viable therapeutic approach for the treatment of dystrophic patients. Additionally, such interventions may serve in mitigating the pathophysiological mechanisms induced by physical inactivity.

Machine Learning-Based Identification of Diagnostic Biomarkers for Korean Male Sarcopenia Through Integrative DNA Methylation and Methylation Risk Score: From the Korean Genomic Epidemiology Study (KoGES).

Sarcopenia, characterized by a progressive decline in muscle mass, strength, and function, is primarily attributable to aging. DNA methylation, influenced by both genetic predispositions and environmental exposures, plays a significant role in sarcopenia occurrence. This study employed machine learning (ML) methods to identify differentially methylated probes (DMPs) capable of diagnosing sarcopenia in middle-aged individuals. We also investigated the relationship between muscle strength, muscle mass, age, and sarcopenia risk as reflected in methylation profiles. Data from 509 male participants in the urban cohort of the Korean Genome Epidemiology Study_Health Examinee study were categorized into quartile groups based on the sarcopenia criteria for appendicular skeletal muscle index (ASMI) and handgrip strength (HG). To identify diagnostic biomarkers for sarcopenia, we used recursive feature elimination with cross validation (RFECV), to pinpoint DMPs significantly associated with sarcopenia. An ensemble model, leveraging majority voting, was utilized for evaluation. Furthermore, a methylation risk score (MRS) was calculated, and its correlation with muscle strength, function, and age was assessed using likelihood ratio analysis and multinomial logistic regression. Participants were classified into two groups based on quartile thresholds: sarcopenia (n = 37) with ASMI and HG in the lowest quartile, and normal ranges (n = 48) in the highest. In total, 238 DMPs were identified and eight probes were selected using RFECV. These DMPs were used to build an ensemble model with robust diagnostic capabilities for sarcopenia, as evidenced by an area under the receiver operating characteristic curve of 0.94. Based on eight probes, the MRS was calculated and then validated by analyzing age, HG, and ASMI among the control group (n = 424). Age was positively correlated with high MRS (coefficient, 1.2494; odds ratio [OR], 3.4882), whereas ASMI and HG were negatively correlated with high MRS (ASMI coefficient, -0.4275; OR, 0.6521; HG coefficient, -0.3116; OR, 0.7323). Overall, this study identified key epigenetic markers of sarcopenia in Korean males and developed a ML model with high diagnostic accuracy for sarcopenia. The MRS also revealed significant correlations between these markers and age, HG, and ASMI. These findings suggest that both diagnostic models and the MRS can play an important role in managing sarcopenia in middle-aged populations.

KL-Biome (Postbiotic Formulation of Lactiplantibacillus plantarum KM2) Improves Dexamethasone-Induced Muscle Atrophy in Mice

Sarcopenia refers to an age-related decrease in muscle mass and strength. The gut–muscle axis has been proposed as a promising target to alleviate muscle atrophy. The effect of KL-Biome—a postbiotic preparation comprising heat-killed Lactiplantibacillus plantarum KM-2, its metabolites, and an excipient (soybean powder)—on muscle atrophy was evaluated using dexamethasone (DEX)-induced atrophic C2C12 myoblasts and C57BL/6J mice. KL-Biome significantly downregulated the expression of genes (Atrogin-1 and MuRF1) associated with skeletal muscle degradation but increased the anabolic phosphorylation of FoxO3a, Akt, and mTOR in C2C12 cells. Oral administration of KL-Biome (900 mg/kg) for 8 weeks significantly improved muscle mass, muscle function, and serum lactate dehydrogenase levels in DEX-treated mice. KL-Biome administration increased gut microbiome diversity and reversed DEX-mediated gut microbiota alterations. Furthermore, it significantly increased the relative abundances of the genera Subdologranulum, Alistipes, and Faecalibacterium prausnitzii, which are substantially involved in short-chain fatty acid production. These findings suggest that KL-Biome exerts beneficial effects on muscle atrophy by regulating gut microbiota.

Mitochondrial Adaptation in Skeletal Muscle: Impact of Obesity, Caloric Restriction, and Dietary Compounds.

PURPOSEOF REVIEW: The global obesity epidemic has become a major public health concern, necessitating comprehensive research into its adverse effects on various tissues within the human body. Among these tissues, skeletal muscle has gained attention due to its susceptibility to obesity-related alterations. Mitochondria are primary source of energy production in the skeletal muscle. Healthy skeletal muscle maintains constant mitochondrial content through continuous cycle of synthesis and degradation. However, obesity has been shown to disrupt this intricate balance. This review summarizes recent findings on the impact of obesity on skeletal muscle mitochondria structure and function. In addition, we summarize the molecular mechanism of mitochondrial quality control systems and how obesity impacts these systems. RECENT FINDINGS: Recent findings show various interventions aimed at mitigating mitochondrial dysfunction in obese model, encompassing strategies including caloric restriction and various dietary compounds. Obesity has deleterious effect on skeletal muscle mitochondria by disrupting mitochondrial biogenesis and dynamics. Caloric restriction, omega-3 fatty acids, resveratrol, and other dietary compounds enhance mitochondrial function and present promising therapeutic opportunities.

Proposal and validation of a new approach in tele-rehabilitation with 3D human posture estimation: a randomized controlled trial in older individuals with sarcopenia

ObjectiveThrough a randomized controlled trial on older adults with sarcopenia, this study compared the training effects of an AI-based remote training group using deep learning-based 3D human pose estimation technology with those of a face-to-face traditional training group and a general remote training group.MethodsSeventy five older adults with sarcopenia aged 60–75 from community organizations in Changchun city were randomly divided into a face-to-face traditional training group (TRHG), a general remote training group (GTHG), and an AI-based remote training group (AITHG). All groups underwent a 3-month program consisting of 24-form Taichi exercises, with a frequency of 3 sessions per week and each session lasting 40 min. The participants underwent Appendicular Skeletal Muscle Mass Index (ASMI), grip strength, 6-meter walking pace, Timed Up and Go test (TUGT), and quality of life score (QoL) tests before the experiment, during the mid-term, and after the experiment. This study used SPSS26.0 software to perform one-way ANOVA and repeated measures ANOVA tests to compare the differences among the three groups. A significance level of p < 0.05 was defined as having significant difference, while p < 0.01 was defined as having a highly significant difference.Results(1) The comparison between the mid-term and pre-term indicators showed that TRHG experienced significant improvements in ASMI, 6-meter walking pace, and QoL (p < 0.01), and a significant improvement in TUGT timing test (p < 0.05); GTHG experienced extremely significant improvements in 6-meter walking pace and QoL (p < 0.01); AITHG experienced extremely significant improvements in ASMI, 6-meter walking pace, and QoL (p < 0.01), and a significant improvement in TUGT timing test (p < 0.05). (2) The comparison between the post-term and pre-term indicators showed that TRHG experienced extremely significant improvements in TUGT timing test (p < 0.01); GTHG experienced significant improvements in ASMI and TUGT timing test (p < 0.05); and AITHG experienced extremely significant improvements in TUGT timing test (p < 0.01). (3) During the mid-term, there was no significant difference among the groups in all tests (p > 0.05). The same was in post-term tests (p > 0.05).ConclusionCompared to the pre-experiment, there was no significant difference at the post- experiment in the recovery effects on the muscle quality, physical activity ability, and life quality of patients with sarcopenia between the AI-based remote training group and the face-to-face traditional training group. 3D pose estimation is equally as effective as traditional rehabilitation methods in enhancing muscle quality, functionality and life quality in older adults with sarcopenia.Trial registrationThe trial was registered in ClinicalTrials.gov (NCT05767710).

The Relationship Between Postural Torticollis Abnormalities and Plagiocephaly on the Early Motor Development Milestones of Lying and Rolling Activities in Infants: A Retrospective Study

ABSTRACT The study examined how neck muscle imbalance and plagiocephaly affect the lying and rolling activities in 118 infants aged 4 to 6 months with postural torticollis. Outcome measures included age, sex, cervical movement, and plagiocephaly severity. Neck muscle function was assessed with the Muscle Function Scale (MFS), and infant motor abilities in lying and rolling were evaluated through the corresponding dimensions of the Gross Motor Function Measure (GMFM). Multiple regression analysis showed that a better MFS score of the affected neck was significantly associated with improved lying and rolling activities in the GMFM (p < .01), and importantly, the interaction between the plagiocephaly and the MFS scores of the affected neck muscle in these activities was found to be significant (p < .05). These results highlight the need for early intervention in infants with torticollis to address muscle imbalance and plagiocephaly, crucial for early motor development (KCT0008367).

Contribution of transient receptor potential vanilloid 1 (TRPV1) channel to cholinergic contraction of rat bladder smooth muscle.

Transient receptor potential vanilloid 1 (TRPV1) is a calcium-permeable ion channel that is gated by the pungent constituent of red chili pepper, capsaicin, and by related chemicals from the group of vanilloids, in addition to noxious heat. It is expressed mostly in sensory neurons to act as a detector of painful stimuli produced by pungent chemicals and high temperatures. Although TRPV1 is also found outside the sensory nervous system, its expression and function in the bladder detrusor smooth muscle (DSM) remain controversial. Here, by using Ca2+ imaging and patch clamp on isolated rat DSM cells, in addition to tensiometry on multicellular DSM strips, we show that TRPV1 is expressed functionally in only a fraction of DSM cells, in which it acts as an endoplasmic reticulum Ca2+-release channel responsible for the capsaicin-activated [Ca2+]i rise. Carbachol-stimulated contractions of multicellular DSM strips contain a TRPV1-dependent component, which is negligible in the circular DSM but reaches ≤50% in the longitudinal DSM. Activation of TRPV1 in rat DSM during muscarinic cholinergic stimulation is ensured by phospholipase A2-catalysed derivation of arachidonic acid and its conversion by lipoxygenases to eicosanoids, which act as endogenous TRPV1 agonists. Immunofluorescence detection of TRPV1 protein in bladder sections and isolated DSM cells confirmed both its preferential expression in the longitudinal DSM sublayer and its targeting to the endoplasmic reticulum. We conclude that TRPV1 is an essential contributor to the cholinergic contraction of bladder longitudinal DSM, which might be important for producing spatial and/or temporal anisotropy of bladder wall deformation in different regions during parasympathetic stimulation. KEY POINTS: The transient receptor potential vanilloid 1 (TRPV1) heat/capsaicin receptor/channel is localized in the endoplasmic reticulum membrane of detrusor smooth muscle (DSM) cells of the rat bladder, operating as a calcium-release channel. Isolated DSM cells are separated into two nearly equal groups, within which the cells either show or do not show TRPV1-dependent [Ca2+]i rise. Carbachol-stimulated, muscarinic ACh receptor-mediated contractions of multicellular DSM strips contain a TRPV1-dependent component. This component is negligible in the circular DSM but reaches ≤50% in longitudinal DSM. Activation of TRPV1 in rat DSM during cholinergic stimulation involves phospholipase A2-catalysed derivation of arachidonic acid and its conversion by lipoxygenases to eicosanoids, which act as endogenous TRPV1 agonists.

Nicotinamide N-methyltransferase inhibition mimics and boosts exercise-mediated improvements in muscle function in aged mice

Human hallmarks of sarcopenia include muscle weakness and a blunted response to exercise. Nicotinamide N-methyltransferase inhibitors (NNMTis) increase strength and promote the regenerative capacity of aged muscle, thus offering a promising treatment for sarcopenia. Since human hallmarks of sarcopenia are recapitulated in aged (24-month-old) mice, we treated mice from 22 to 24 months of age with NNMTi, intensive exercise, or a combination of both, and compared skeletal muscle adaptations, including grip strength, longitudinal running capacity, plantarflexor peak torque, fatigue, and muscle mass, fiber type, cross-sectional area, and intramyocellular lipid (IMCL) content. Exhaustive proteome and metabolome analyses were completed to identify the molecular mechanisms underlying the measured changes in skeletal muscle pathophysiology. Remarkably, NNMTi-treated aged sedentary mice showed ~ 40% greater grip strength than sedentary controls, while aged exercised mice only showed a 20% increase relative to controls. Importantly, the grip strength improvements resulting from NNMTi treatment and exercise were additive, with NNMTi-treated exercised mice developing a 60% increase in grip strength relative to sedentary controls. NNMTi treatment also promoted quantifiable improvements in IMCL content and, in combination with exercise, significantly increased gastrocnemius fiber CSA. Detailed skeletal muscle proteome and metabolome analyses revealed unique molecular mechanisms associated with NNMTi treatment and distinct molecular mechanisms and cellular processes arising from a combination of NNMTi and exercise relative to those given a single intervention. These studies suggest that NNMTi-based drugs, either alone or combined with exercise, will be beneficial in treating sarcopenia and a wide range of age-related myopathies.

The impact of diffusion tensor imaging tractography settings on muscle fascicle architecture and diffusion parameter estimates: Tract length, completion, and curvature are most sensitive to tractography settings.

Diffusion-tensor (DT)-MRI tractography provides information about properties relevant to muscle health and function, including estimates of architectural properties such as fascicle length, pennation angle, and curvature and diffusion properties such as mean diffusivity (MD) and fractional anisotropy (FA). Tractography settings, including integration algorithms, thresholds for early tract termination, and tract smoothing approaches, impact the accuracy of the muscle property estimates. However, muscle DT-MRI tractography is performed using a variety of these settings, complicating comparisons between different studies. The effects of different tractography settings on muscle architecture estimates have not been fully explored, and optimized settings for muscle tractography have not yet been determined. We examined the influence of integration algorithm and termination check settings combined with a range of step sizes, termination criteria, and smoothing polynomial orders on tract characteristics, completion/reason for termination, and goodness of fit between fiber tracts and smoothing polynomials using 3-T DT-MR images of the lower leg muscles of seven healthy adults. We found that tract length and completion were highly sensitive to strict FA and intersegment angle thresholds (25%-69% reduction in complete fiber tracts from lowest to highest minimum FA threshold and 11%-36% reduction from highest to lowest intersegment angle threshold). Higher order polynomials (third and fourth order vs. second order) better fit the muscle fiber trajectories, but curvature estimates were highly sensitive to smoothing polynomial order (3.9-6.6 m-1 increase for second- vs. fourth-order fitting polynomials). Step size impacted curvature estimates, albeit to a lesser degree. Integration algorithm had little impact, and mean pennation angle, and tract-based FA and MD, were relatively insensitive to all parameters. The results demonstrate which muscle diffusion measures and architectural estimates are most sensitive to varying tractography settings and support the need for consistent reporting of tractography details to aid interpretation and comparison of results between studies.

Hindlimb immobilization induces insulin resistance and elevates mitochondrial ROS production in the hippocampus of female rats.

Alzheimer's Disease (AD) is the 5th leading cause of death in older adults and treatment options are severely lacking. Recent findings demonstrate a strong relationship between skeletal muscle and cognitive function, with evidence supporting that muscle quality and cognitive function are positively correlated in older adults. Conversely, decreased muscle function is associated with a 3-fold increased risk of cognitive decline. Based on these observations, the purpose of this study was to investigate the negative effects of muscle disuse (via a model of hindlimb immobilization (HLI)) on hippocampal insulin sensitivity and mitochondrial function and identify the potential mechanisms involved. HLI for 10 days in 4-month-old female Wistar rats resulted in the following novel findings: 1) hippocampal insulin resistance and deficits in whole body glucose homeostasis, 2) dramatically increased mitochondrial reactive oxygen species (ROS) production in the hippocampus, 3) elevated markers for amyloidogenic cleavage of APP and tau protein in the hippocampus, 4) and reduced BDNF expression. These findings were associated with global changes in iron homeostasis, with muscle disuse producing muscle iron accumulation in association with decreased serum and whole brain iron levels. We report the novel finding that muscle disuse alters brain iron homeostasis and reveal a strong negative correlation between muscle and brain iron content. Overall, HLI-induced muscle disuse has robust negative effects on hippocampal insulin sensitivity and ROS production in association with altered brain iron homeostasis. This work provides potential novel mechanisms that may help explain how loss of muscle function contributes to cognitive decline and AD risk.

No association between vascular aging and sarcopenia in healthy participants

Background & AimsSeveral reports inform an association between vascular aging and sarcopenia. However, both conditions appear along with aging. Therefore, their association may be circumstantial and not casually linked. Our aim was to determine if individuals with higher-than-expected vascular aging have a higher frequency of sarcopenia. MethodsIn 802 participants we calculated the association between pulse wave pressure and carotid intima media thickness and age and blood pressure, to derive predictive regression equations. In 161 of these participants we measured body composition by double beam X ray absorptiometry (DEXA), hand grip strength, rectus femoris thickness by ultrasound, activity energy expenditure by actigraphy and peak oxygen consumption and workload in an incremental exercise test. We calculated their expected values for pulse wave velocity and carotid intima media thickness and compared muscle mass and function between those with higher or lower than expected parameters. In 60 of these participants, we measured body composition sequentially to assess its change over time. ResultsAge and blood pressure predicted the variance of pulse wave velocity and carotid intima media thickness with R2 values of 0.94 to 0.97 and 0.54 to 0.66, respectively. No differences in the frequency of sarcopenia and in muscle mass and strength were observed between participants with higher or lower than expected pulse wave velocity and carotid intima media thickness. In the group with sequential assessments, no differences in the change of muscle mass over time were observed in participants with and without accelerated vascular aging. ConclusionsWe were not able to find an association between vascular aging and sarcopenia

Clinical benefit of botulinum toxin for treatment of persistent TMD-related myofascial pain: A randomized, placebo-controlled, cross-over trial.

Injections of botulinum toxin type A (BoNT-A) have been proposed as an additional treatment modality for patients suffering chronic temporomandibular disorder (TMD)-related myofascial pain (MFP). BoNT-A impairs muscle function, along with its analgesic effect, and a minimal effective dose should be used. The objective of this randomized placebo-controlled crossover study was to evaluate the clinical benefit of a moderate dose (50 U) of BoNT-A. Sixty-six subjects were randomized into two groups, one which received BoNT-A first and a second which received a saline solution (SS) first. Follow-ups were performed 2, 11, and 16 weeks after the injections. Diagnostic criteria for temporomandibular disorders (DC/TMD) diagnostic algorithms were used to evaluate characteristic pain intensity (CPI) and pain-related disability based on the Graded Chronic Pain Scale (GCPS). Electromyographic and bite force were also evaluated. The within-group analysis showed a significant improvement in pain intensity and pain-related disability after BoNT-A (p < 0.001, p = 0.005, p = 0.011) and SS (p = 0.003, p = 0.005, p = 0.046) injections up to week 16. The between-group analysis of pain-related variables revealed no differences between groups at any time. Nonetheless, BoNT-A, but not SS, caused a significant decline in muscle performance. The number needed to treat (NNT) regarding a clinically significant pain reduction (≥30%) was 6.3, 57.0, and 19.0 at 2, 11, and 16-week follow-ups favoring BoNT-A. Injections of 50 U of BoNT-A might improve MFP symptoms, but the specific effect of the drug on pain compared to the placebo is not obvious.

A Comparative Study between Ultrasound Guided Interscalene and Ultrasound Guided Suprascapular Nerve Blocks in Postoperative Pain and Hand Motor Power Affection in Shoulder Scope Surgeries

Abstract Background Interscalene approach of brachial plexus nerve block is recognized as the gold standard technique for postoperative pain control after shoulder scope surgeries. However, it is associated with major adverse effects and patient discomfort due to paralysis of the hand muscles. The suprascapular nerve block is considered to be a safe and effective alternative to interscalene nerve block for shoulder surgery without affecting the motor function of the hand muscles and other serious complications of interscalene nerve block, especially in ambulatory surgery. Aim of the work The aim of this study is to compare interscalene and suprascapular nerve block in terms of postoperative pain, opioid consumption, and hand grip strength in shoulderscopic surgeries. Patients and Methods This prospective, randomized trial was done in Ain Shams University Hospitals. A sample of 50 patients; 25 patients in each group, namely Group ISB (interscalene approach of brachial plexus block) and Group SSNB (suprascapular nerve block). Visual Analogue Scale (VAS) was used to assess Shoulder pain at rest and upon flexion in the first 24 hours. The degree of hand motor power affection, the total amount of opioids used as rescue analgesia, and the incidence of complications were also recorded. Results The findings revealed no statistically significant difference between groups (p-value &amp;gt; 0.05) in pain control all over the 24 hours by VAS score at rest and at arm flexion. SSNB received a larger total narcotic dose (60±26.02) mg of pethidine than ISB (52±22.73). However, there was no statistical difference between them throughout the 24 hours regarding total narcotic consumption and 1st time for pethidine administration. The ISB group showed a statistically significant reduction in the hand power grip strength postoperatively (83.68±4.75 %). Conclusions The results of the present study favour SSNB as the first choice of pain control after shoulderscopic surgeries for a patient scheduled for early home discharge because of the complete recovery of the hand muscles’ motor power.

FOXO-regulated DEAF1 controls muscle regeneration through autophagy

ABSTRACT The commonality between various muscle diseases is the loss of muscle mass, function, and regeneration, which severely restricts mobility and impairs the quality of life. With muscle stem cells (MuSCs) playing a key role in facilitating muscle repair, targeting regulators of muscle regeneration has been shown to be a promising therapeutic approach to repair muscles. However, the underlying molecular mechanisms driving muscle regeneration are complex and poorly understood. Here, we identified a new regulator of muscle regeneration, Deaf1 (Deformed epidermal autoregulatory factor-1) – a transcriptional factor downstream of foxo signaling. We showed that Deaf1 is transcriptionally repressed by FOXOs and that DEAF1 targets to Pik3c3 and Atg16l1 promoter regions and suppresses their expression. Deaf1 depletion therefore induces macroautophagy/autophagy, which in turn blocks MuSC survival and differentiation. In contrast, Deaf1 overexpression inactivates autophagy in MuSCs, leading to increased protein aggregation and cell death. The fact that Deaf1 depletion and its overexpression both lead to defects in muscle regeneration highlights the importance of fine tuning DEAF1-regulated autophagy during muscle regeneration. We further showed that Deaf1 expression is altered in aging and cachectic MuSCs. Manipulation of Deaf1 expression can attenuate muscle atrophy and restore muscle regeneration in aged mice or mice with cachectic cancers. Together, our findings unveil an evolutionarily conserved role for DEAF1 in muscle regeneration, providing insights into the development of new therapeutic strategies against muscle atrophy.

Association of lipid-lowering drugs with risk of sarcopenia: a drug target mendelian randomization study and meta-analysis

BackgroundLipid-lowering drugs are widely used among the elderly, with some studies suggesting links to muscle-related symptoms. However, the causality remains uncertain.MethodsUsing the Mendelian randomization (MR) approach, we assessed the causal effects of genetically proxied reduced low-density lipoprotein cholesterol (LDL-C) through inhibitions of hydroxy-methyl-glutaryl-CoA reductase (HMGCR), proprotein convertase subtilisin/kexin type 9 (PCSK9), and Niemann-Pick C1-like 1 (NPC1L1) on sarcopenia-related traits, including low hand grip strength, appendicular lean mass, and usual walking pace. A meta-analysis was conducted to combine the causal estimates from different consortiums.ResultsUsing LDL-C pooled data predominantly from UK Biobank, genetically proxied inhibition of HMGCR was associated with higher appendicular lean mass (beta = 0.087, P = 7.56 × 10− 5) and slower walking pace (OR = 0.918, P = 6.06 × 10− 9). In contrast, inhibition of PCSK9 may reduce appendicular lean mass (beta = -0.050, P = 1.40 × 10− 3), while inhibition of NPC1L1 showed no causal impact on sarcopenia-related traits. These results were validated using LDL-C data from Global Lipids Genetics Consortium, indicating that HMGCR inhibition may increase appendicular lean mass (beta = 0.066, P = 2.17 × 10− 3) and decelerate walking pace (OR = 0.932, P = 1.43 × 10− 6), whereas PCSK9 inhibition could decrease appendicular lean mass (beta = -0.048, P = 1.69 × 10− 6). Meta-analysis further supported the robustness of these causal associations.ConclusionsGenetically proxied HMGCR inhibition may increase muscle mass but compromise muscle function, PCSK9 inhibition could result in reduced muscle mass, while NPC1L1 inhibition is not associated with sarcopenia-related traits and this class of drugs may serve as viable alternatives to sarcopenia individuals or those at an elevated risk.

Cardiac and skeletal muscle manifestations in the G608G mouse model of Hutchinson-Gilford progeria syndrome.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder resulting from de novo mutations in the lamin A gene. Children with HGPS typically pass away in their teenage years due to cardiovascular diseases such as atherosclerosis, myocardial infarction, heart failure, and stroke. In this study, we characterized the G608G HGPS mouse model and explored cardiac and skeletal muscle function, along with senescence-associated phenotypes in fibroblasts. Homozygous G608G HGPS mice exhibited cardiac dysfunction, including decreased cardiac output and stroke volume, and impaired left ventricle relaxation. Additionally, skeletal muscle exhibited decreased isometric tetanic torque, muscle atrophy, and increased fibrosis. HGPS fibroblasts showed nuclear abnormalities, decreased proliferation, and increased expression of senescence markers. These findings provide insights into the pathophysiology of the G608G HGPS mouse model and inform potential therapeutic strategies for HGPS.

Evaluation of masticatory muscle function in the treatment dynamics of patients with myofascial pain syndrome

Relevance. Myofascial pain syndrome (MPS) often progresses to a chronic form that is challenging to treat with established methods. This issue is well known to dentists and frequently leads to frustration despite significant efforts to advance knowledge in the fields of etiopathogenesis, diagnosis, and therapy. Most treatment protocols focus on normalizing physiological parameters, such as restoring masticatory function, achieving stable occlusal relationships, alleviating pain, and enhancing the psychological well-being of these patients. Therefore, the need for non-invasive diagnostics to assess functional activity and monitor the condition of masticatory muscles during treatment is crucial. This study aims to address this need.Materials and methods. The examination and treatment of 64 patients with myofascial pain syndrome were conducted in two stages—clinical and electromyographic. During the clinical examination, tenderness of the masticatory muscles during palpation and the degree of mouth opening were assessed. The electromyographic research was also conducted in two stages. The first stage assessed the average amplitude and total biopotential of the masticatory and temporal muscles on both the right and left sides. The second stage evaluated the symmetry index of the masticatory muscles, as well as torsion and masseter indices. The first group received conventional treatment combined with laser therapy, while the second group received ozone therapy and kinesiology taping in addition to the conventional therapy.Results. In the short-term observations over 14 days, both groups achieved positive results. However, patients undergoing ozone therapy and kinesiology taping showed statistically significant improvements in their parameters by the third day of observation compared to their baseline values.Conclusion. For diagnosing this pathology, it is advisable to incorporate electromyography into the examination protocol to allow non-invasive evaluation of the functional activity of the masticatory muscles. For treating myofascial pain syndrome, minimally invasive methods with anti-inflammatory, analgesic, and muscle relaxant effects are recommended. While all treatment methods yielded favorable results, ozone therapy combined with kinesiology taping effectively eliminated both subjective and objective symptoms in this patient category.

Acute Effect of Transcranial Direct Current Stimulation in Pelvic Floor Muscle Function in Young Healthy Women: Initial Findings of a Randomized Controlled Trial.

Transcranial direct current stimulation (tDCS) can enhance muscle function in healthy individuals. However, it is unknown if tDCS associated with pelvic floor muscle training (PFMT) can improve pelvic floor muscle function (PFMF) in healthy women. The aim of this study was to investigate the acute effect of a single session of tDCS in PFMF compared with sham-tDCS in healthy women. A double-blind, cross-over, randomized clinical trial was conducted with healthy, nulliparous and sexually active women. PFMF was assessed by bidigital palpation (PERFECT scale) and intravaginal pressure by a manometer (Peritron™). Participants randomly underwent two tDCS sessions (active and sham) 7 days apart. The electrode was positioned equal for both protocols, the anode electrode in the supplementary motor area (M1) and the cathode electrode in the right supraorbital frontal cortex (Fp2). The current was applied for 20min at 2mA in active stimulation and for 30s in sham-tDCS. The tDCS applications were associated with verbal instructions to PFMT in a seated position. After each tDCS session PFMF was reevaluated. Twenty young healthy women (aged 23.4 ± 1.7years; body mass index 21.7 ± 2.2kg/m2) were included. No difference was observed in power, endurance, and intravaginal pressure of PFMF (p > 0.05). The number of sustained contractions improved from 3.0 (2.0-3.5) to 4.0 (3.0-5.0) after active-tDCS (p = 0.0004) and was superior to sham-tDCS (p = 0.01). The number of sustained contractions of PFM improved immediately after a single active-tDCS session, with a difference compared with the post-intervention result of sham-tDCS in healthy young women.