Resistance training in women with myotonic dystrophy type 1: a multisystemic therapeutic avenue.

Myotonic dystrophy type 1 (DM1) is a hereditary disease characterized by muscular impairments. Fundamental and clinical positive effects of strength training have been reported in men with DM1, but its impact on women remains unknown. We evaluated the effects of a 12-week supervised strength training on physical and neuropsychiatric health. Women with DM1 performed a twice-weekly supervised resistance training program (3 series of 6-8 repetitions of squat, leg press, plantar flexion, knee extension, and hip abduction). Lower limb muscle strength, physical function, apathy, anxiety and depression, fatigue and excessive somnolence, pain, and patient-reported outcomes were assessed before and after the intervention, as well as three and six months after completion of the training program. Muscle biopsies of the vastus lateralis were also taken before and after the training program to assess muscle fiber growth. Eleven participants completed the program (attendance: 98.5 %). Maximal hip and knee extension strength (p < 0.006), all One-Repetition Maximum strength measures (p < 0.001), apathy (p = 0.0005), depression (p = 0.02), pain interference (p = 0.01) and perception of the lower limb function (p = 0.003) were significantly improved by training. Some of these gains were maintained up to six months after the training program. Strength training is a good therapeutic strategy for women with DM1.

Towards the Identification of Biomarkers for Muscle Function Improvement in Myotonic Dystrophy Type 1.

BACKGROUND: Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy in adults. In DM1 patients, skeletal muscle is severely impaired, even atrophied and patients experience a progressive decrease in maximum strength. Strength training for these individuals can improve their muscle function and mass, however, the biological processes involved in these improvements remain unknown. OBJECTIVE: This exploratory study aims at identifying the proteomic biomarkers and variables associated with the muscle proteome changes induced by training in DM1 individuals. METHODS: An ion library was developed from liquid chromatography-tandem mass spectrometry proteomic analyses of Vastus Lateralis muscle biopsies collected in 11 individuals with DM1 pre-and post-training. RESULTS: The proteomic analysis showed that the levels of 44 proteins were significantly modulated. A literature review (PubMed, UniProt, PANTHER, REACTOME) classified these proteins into biological sub-classes linked to training-induced response, including immunity, energy metabolism, apoptosis, insulin signaling, myogenesis and muscle contraction. Linear models identified key variables explaining the proteome modulation, including atrophy and hypertrophy factors. Finally, six proteins of interest involved in myogenesis, muscle contraction and insulin signaling were identified: calpain-3 (CAN3; Muscle development, positive regulation of satellite cell activation), 14-3-3 protein epsilon (1433E; Insulin/Insulin-like growth factor, PI3K/Akt signaling), myosin-binding protein H (MYBPH; Regulation of striated muscle contraction), four and a half LIM domains protein 3 (FHL3; Muscle organ development), filamin-C (FLNC; Muscle fiber development) and Cysteine and glycine-rich protein 3 (CSRP3). CONCLUSION: These findings may lead to the identification for DM1 individuals of novel muscle biomarkers for clinical improvement induced by rehabilitation, which could eventually be used in combination with a targeted pharmaceutical approach to improving muscle function, but further studies are needed to confirm those results.

Resistance Exercise Training Rescues Mitochondrial Dysfunction in Skeletal Muscle of Patients with Myotonic Dystrophy Type 1.

BACKGROUND: Myotonic dystrophy type 1 (DM1) is a dominant autosomal neuromuscular disorder caused by the inheritance of a CTG triplet repeat expansion in the Dystrophia Myotonica Protein Kinase (DMPK) gene. At present, no cure currently exists for DM1 disease. OBJECTIVE: This study investigates the effects of 12-week resistance exercise training on mitochondrial oxidative phosphorylation in skeletal muscle in a cohort of DM1 patients (n = 11, men) in comparison to control muscle with normal oxidative phosphorylation. METHODS: Immunofluorescence was used to assess protein levels of key respiratory chain subunits of complex I (CI) and complex IV (CIV), and markers of mitochondrial mass and cell membrane in individual myofibres sampled from muscle biopsies. Using control's skeletal muscle fibers population, we classified each patient's fibers as having normal, low or high levels of CI and CIV and compared the proportions of fibers before and after exercise training. The significance of changes observed between pre- and post-exercise within patients was estimated using a permutation test. RESULTS: At baseline, DM1 patients present with significantly decreased mitochondrial mass, and isolated or combined CI and CIV deficiency. After resistance exercise training, in most patients a significant increase in mitochondrial mass was observed, and all patients showed a significant increase in CI and/or CIV protein levels. Moreover, improvements in mitochondrial mass were correlated with the one-repetition maximum strength evaluation. CONCLUSIONS: Remarkably, 12-week resistance exercise training is sufficient to partially rescue mitochondrial dysfunction in DM1 patients, suggesting that the response to exercise is in part be due to changes in mitochondria.

Clearance of defective muscle stem cells by senolytics restores myogenesis in myotonic dystrophy type 1.

Muscle stem cells, the engine of muscle repair, are affected in myotonic dystrophy type 1 (DM1); however, the underlying molecular mechanism and the impact on the disease severity are still elusive. Here, we show using patients' samples that muscle stem cells/myoblasts exhibit signs of cellular senescence in vitro and in situ. Single cell RNAseq uncovers a subset of senescent myoblasts expressing high levels of genes related to the senescence-associated secretory phenotype (SASP). We show that the levels of interleukin-6, a prominent SASP cytokine, in the serum of DM1 patients correlate with muscle weakness and functional capacity limitations. Drug screening revealed that the senolytic BCL-XL inhibitor (A1155463) can specifically remove senescent DM1 myoblasts by inducing their apoptosis. Clearance of senescent cells reduced the expression of SASP, which rescued the proliferation and differentiation capacity of DM1 myoblasts in vitro and enhanced their engraftment following transplantation in vivo. Altogether, this study identifies the pathogenic mechanism associated with muscle stem cell defects in DM1 and opens a therapeutic avenue that targets these defective cells to restore myogenesis.

Individual transcriptomic response to strength training for patients with myotonic dystrophy type 1.

Myotonic dystrophy type 1 (DM1), the most common form of adult-onset muscular dystrophy, is caused by a CTG expansion resulting in significant transcriptomic dysregulation that leads to muscle weakness and wasting. While strength training is clinically beneficial in DM1, molecular effects had not been studied. To determine whether training rescued transcriptomic defects, RNA-Seq was performed on vastus lateralis samples from 9 male patients with DM1 before and after a 12-week strength-training program and 6 male controls who did not undergo training. Differential gene expression and alternative splicing analysis were correlated with the one-repetition maximum strength evaluation method (leg extension, leg press, hip abduction, and squat). While training program-induced improvements in splicing were similar among most individuals, rescued splicing events varied considerably between individuals. Gene expression improvements were highly varied between individuals, and the percentage of differentially expressed genes rescued after training were strongly correlated with strength improvements. Evaluating transcriptome changes individually revealed responses to the training not evident from grouped analysis, likely due to disease heterogeneity and individual exercise response differences. Our analyses indicate that transcriptomic changes are associated with clinical outcomes in patients with DM1 undergoing training and that these changes are often specific to the individual and should be analyzed accordingly.

Functional contribution of mesencephalic locomotor region nuclei to locomotor recovery after spinal cord injury.

Spinal cord injury (SCI) results in a disruption of information between the brain and the spinal circuit. Electrical stimulation of the mesencephalic locomotor region (MLR) can promote locomotor recovery in acute and chronic SCI rodent models. Although clinical trials are currently under way, there is still debate about the organization of this supraspinal center and which anatomic correlate of the MLR should be targeted to promote recovery. Combining kinematics, electromyographic recordings, anatomic analysis, and mouse genetics, our study reveals that glutamatergic neurons of the cuneiform nucleus contribute to locomotor recovery by enhancing motor efficacy in hindlimb muscles, and by increasing locomotor rhythm and speed on a treadmill, over ground, and during swimming in chronic SCI mice. In contrast, glutamatergic neurons of the pedunculopontine nucleus slow down locomotion. Therefore, our study identifies the cuneiform nucleus and its glutamatergic neurons as a therapeutical target to improve locomotor recovery in patients living with SCI.

Impact of a 12-week Strength Training Program on Fatigue, Daytime Sleepiness, and Apathy in Men with Myotonic Dystrophy Type 1.

BACKGROUND: Myotonic dystrophy type 1 (DM1) is a multisystemic neuromuscular disorder causing a plea of impairments, of which fatigue and apathy are some of the most frequent non-muscular symptoms. No curative treatment exists to date, and patients only have access to limited effective care, which are intended to decrease the burden of specific symptoms in daily life. OBJECTIVE: This study aimed to assess whether a 12-week strength training program has an impact on fatigue/daytime sleepiness, apathy, and disease bruden in men with DM1. METHODS: Eleven participants completed the Fatigue and Daytime Sleepiness Scale (FDSS) and the Myotonic Dystrophy Health Index (MDHI) at baseline, at 6 and 12 weeks, and at 6 and 9 months. Also, the Apathy Evaluation Scale (AES) was filled out at baseline, at 12 weeks, and at 6 and 9 months. RESULTS: Results show significant effects of the training program both on apathy and fatigue/daytime sleepiness, effects that are respectively greater at three and six months after the end of the program than at its very end. However, no difference was observed regarding the overall disease burden. CONCLUSION: These findings are promising for patients with DM1 considering that few non-pharmacological treatments are available.

Heterozygous Dcc Mutant Mice Have a Subtle Locomotor Phenotype.

Axon guidance receptors such as deleted in colorectal cancer (DCC) contribute to the normal formation of neural circuits, and their mutations can be associated with neural defects. In humans, heterozygous mutations in DCC have been linked to congenital mirror movements, which are involuntary movements on one side of the body that mirror voluntary movements of the opposite side. In mice, obvious hopping phenotypes have been reported for bi-allelic Dcc mutations, while heterozygous mutants have not been closely examined. We hypothesized that a detailed characterization of Dcc heterozygous mice may reveal impaired corticospinal and spinal functions. Anterograde tracing of the Dcc+/- motor cortex revealed a normally projecting corticospinal tract, intracortical microstimulation (ICMS) evoked normal contralateral motor responses, and behavioral tests showed normal skilled forelimb coordination. Gait analyses also showed a normal locomotor pattern and rhythm in adult Dcc+/- mice during treadmill locomotion, except for a decreased occurrence of out-of-phase walk and an increased duty cycle of the stance phase at slow walking speed. Neonatal isolated Dcc+/- spinal cords had normal left-right and flexor-extensor coupling, along with normal locomotor pattern and rhythm, except for an increase in the flexor-related motoneuronal output. Although Dcc+/- mice do not exhibit any obvious bilateral impairments like those in humans, they exhibit subtle motor deficits during neonatal and adult locomotion.

Assessment of muscular strength and functional capacity in the juvenile and adult myotonic dystrophy type 1 population: a 3-year follow-up study.

INTRODUCTION: Myotonic dystrophy type 1 (DM1) is a progressive, multisystemic, and autosomal dominant disease. Muscle wasting and weakness have been associated with impaired functional capacity and restricted social participation in affected individuals. The disease's presentation is very heterogenous and its progression is still under-documented. OBJECTIVE: The aim of the study was to document the progression of muscular strength and functional capacity in the DM1 population over a 3-year period. METHODS: Twenty-three individuals with juvenile or adult phenotypes of DM1 were recruited to complete clinical assessments in 2016 and 2019. Maximal isometric muscle strength (MIMS) was evaluated with quantified muscle testing and functional capacity was evaluated with the Mini-BESTest, the 10-m walk test at comfortable and maximal speeds, the Timed Up and Go and the 6-min walk test. Participants also completed three questionnaires: DM1-Activ, Upper Extremity Functional Index and Lower Extremity Functional Scale (LEFS). Subgroup analyses were evaluated for sex, phenotype, and type of physical activity practiced during the 3-year period. RESULTS: For the whole group, there was a significant decline in the scores of the Mini-BESTest and the LEFS. Also, MIMS significantly declined for prehension, lateral pinch as well as for hip abductors, knee extensors and ankle dorsiflexors muscle groups. Subgroups analyses revealed that men lost more MIMS than women, and that adult phenotype lost more MIMS than juvenile phenotype. CONCLUSION: Quantified muscle testing is a better indicator of disease progression over a 3-year period than functional tests. Phenotype and sex are important factors that influence the progression of DM1.

Validity of the Mini-BESTest in adults with myotonic dystrophy type 1.

INTRODUCTION: Myotonic dystrophy type 1 (DM1) is a multisystemic neuromuscular disease that causes balance problems. The objective of this study was to assess the construct validity of the Mini-BESTest among adults with DM1. METHODS: Fifty-nine individuals with late-onset or adult phenotypes of DM1 were recruited. Participants performed the Mini-BESTest, 10-Meter Walk Test (10mWT), 6-Minute Walk Test (6MWT), and Timed Up & Go (TUG) and were questioned on their tendency to lose balance and whether they fell in the past month. RESULTS: Scores on the Mini-BESTest were significantly different between phenotypes and CTG repeat numbers (P < .02). Significant correlations were found with the 10mWT, 6MWT, and the TUG (r = 0.77-0.84; P < .001). A cutoff score of 21.5 was found to identify fallers with 90% posttest accuracy. DISCUSSION: The Mini-BESTest demonstrates evidence of construct validity when assessing balance in the DM1 population.

Strength-training effectively alleviates skeletal muscle impairments in myotonic dystrophy type 1.

Myotonic dystrophy type 1 (DM1) is a multisystemic disease characterized by progressive muscle weakness. The aim of this project is to evaluate the effects of a 12-week lower limb strength training program in 11 men with DM1. Maximal isometric muscle strength, 30-second sit-to-stand, comfortable and maximal 10-m walk test (10 mwt) were evaluated at baseline, 6 and 12 weeks, and at 6 and 9 months. The one-repetition maximum strength evaluation method of the training exercises was completed at baseline, 6 and 12 weeks. Muscle biopsies were taken in the vastus lateralis at baseline and 12 weeks to evaluate muscle fiber typing and size (including atrophy/hypertrophy factors). Performance in strength and functional tests all significantly improved by week 12. Maximal isometric muscle strength of the knee extensors decreased by month 9, while improved walking speed and 30 second sit-to-stand performance were maintained. On average, there were no significant changes in fiber typing or size after training. Further analysis showed that individual abnormal hypertrophy factor at baseline could explain the different changes in muscle size among participants. Strength training induces maximal isometric muscle strength and lasting functional gains in DM1. Abnormal hypertrophy factor could be a key component to identify high and low responders to hypertrophy in DM1.

Training program-induced skeletal muscle adaptations in two men with myotonic dystrophy type 1.

OBJECTIVE: The purpose of this side product of another unpublished research project, was to address the effects of a training program on skeletal muscle adaptations of people with myotonic dystrophy type 1 (DM1), under a multifaceted perspective. The objective of this study was to look at training induced muscular adaptations by evaluating changes in muscle strength, myofiber cross-sectional area (CSA), proportion of myofiber types and with indirect markers of muscle growth [proportion of centrally nucleated fibers (CNF) and density of neutrophils and macrophages]. Two men with DM1 underwent a 12-week strength/endurance training program (18 sessions). Two muscle biopsies were obtained pre- and post-training program. RESULTS: Muscular adaptations occurred only in Patient 1, who attended 72% of the training sessions compared to 39% for Patient 2. These adaptations included increase in the CSA of type I and II myofibers and changes in their proportion. No changes were observed in the percentage of CNF, infiltration of neutrophils and macrophages and muscle strength. These results illustrate the capacity of skeletal muscle cells to undergo adaptations linked to muscle growth in DM1 patients. Also, these adaptations seem to be dependent on the attendance. Trial registration Clinicaltrials.gov NCT04001920 retrospectively registered on June 26th, 2019.

Correction to: What is known about the effects of exercise or training to reduce skeletal muscle impairments of patients with myotonic dystrophy type 1? A scoping review.

An incorrect attribution of the first study regarding the effect of exercise in DM1 mouse models needs to be revised.

Intra-Rater Reliability and Concurrent Validity of Quantified Muscle Testing for Maximal Knee Extensors Strength in Men with Myotonic Dystrophy Type 1.

BACKGROUND: Myotonic dystrophy type 1 (DM1) is the most prevalent degenerative neuromuscular disease in adults. Knee extensor (KE) maximal strength loss is a strong indicator of physical limitations in DM1. A reliable, precise and accessible maximal strength evaluation method needs to be validated for this slowly progressive disease. OBJECTIVE: This paper aims to assess the intra-rater reliability, the standard error of measurement (SEM), the minimal detectable change (MDC), and the concurrent validity of quantified muscle testing (QMT) using a handheld dynamometer with a gold standard: the Biodex isokinetic device. METHODS: Nineteen men with the adult form of DM1 participated in this study by attending 2 visits spaced by one week. The evaluation of KE muscle strength with QMT was completed on the first visit and the same QMT evaluation in addition to the maximal muscle strength evaluation using an isokinetic device were performed on the second visit. RESULTS: The intra-rater reliability was excellent with an intraclass correlation coefficient (ICC) of 0.98 (0.96-0.99 : 95% confidence interval). SEM and MDC values were 1.05 Nm and 2.92 Nm, respectively. Concurrent validity of QMT of KE muscle group with the Biodex was also excellent with a Spearman's correlation of ρ= 0.98. CONCLUSIONS: The excellent concurrent validity and intra-rater reliability, and the small SEM and MDC of the QMT make this test a method of choice, in either a clinical or research setting, to precisely evaluate muscle strength impairments of the KE in men with DM1.

What is known about the effects of exercise or training to reduce skeletal muscle impairments of patients with myotonic dystrophy type 1? A scoping review.

BACKGROUND: Myotonic dystrophy type 1 (DM1) is a neuromuscular disease characterized by multisystemic involvements including a progressive loss of maximal muscle strength and muscle wasting. Poor lower-limb strength is an important factor explaining disrupted social participation of affected individuals. This review aims to map what is known about the effects of exercise and training programs undertaken to counteract skeletal muscle impairments in DM1 patients. METHODS: Medline, CINAHL and EMBASE databases were searched. Regarding study eligibility, title and abstract of 704 studies followed by 45 full articles were reviewed according to the following eligibility criteria. Inclusion: (1) humans with DM1 and (2) experimental protocol relying on exercise or training. Exclusion: (1) studies that do not evaluate skeletal muscle responses or adaptations, (2) reviews covering articles already included and (3) pharmacological intervention at the same time of exercise or training program. RESULTS: Twenty-one papers were selected for in-depth analysis. Different exercise or training protocols were found including: acute exercise, neuromuscular electric stimulation, strength training, aerobic training, balance training and multiple rehabilitation interventions. Seven studies reported clinical measurements only, five physiological parameters only and nine both types. CONCLUSION: This scoping review offers a complete summary of the current scientific literature on the effect of exercise and training in DM1 and a framework for future studies based on the concomitant evaluation of the several outcomes in present literature. Although there were a good number of studies focusing on clinical measurements, heterogeneity between studies does not allow to identify what are the adequate training parameters to obtain exercise or training-induced positive impacts on muscle function. Scientific literature is even more scarce regarding physiological parameters, where much more research is needed to understand the underlying mechanisms of exercise response in DM1.

Distinct Contributions of Mesencephalic Locomotor Region Nuclei to Locomotor Control in the Freely Behaving Mouse.

The mesencephalic locomotor region (MLR) has been initially identified as a supraspinal center capable of initiating and modulating locomotion. Whereas its functional contribution to locomotion has been widely documented throughout the phylogeny from the lamprey to humans, there is still debate about its exact organization. Combining kinematic and electrophysiological recordings in mouse genetics, our study reveals that glutamatergic neurons of the cuneiform nucleus initiate locomotion and induce running gaits, whereas glutamatergic and cholinergic neurons of the pedunculopontine nucleus modulate locomotor pattern and rhythm, contributing to slow-walking gaits. By initiating, modulating, and accelerating locomotion, our study identifies and characterizes distinct neuronal populations of this functional region important to locomotor command.

Speed-Dependent Modulation of the Locomotor Behavior in Adult Mice Reveals Attractor and Transitional Gaits.

Locomotion results from an interplay between biomechanical constraints of the muscles attached to the skeleton and the neuronal circuits controlling and coordinating muscle activities. Quadrupeds exhibit a wide range of locomotor gaits. Given our advances in the genetic identification of spinal and supraspinal circuits important to locomotion in the mouse, it is now important to get a better understanding of the full repertoire of gaits in the freely walking mouse. To assess this range, young adult C57BL/6J mice were trained to walk and run on a treadmill at different locomotor speeds. Instead of using the classical paradigm defining gaits according to their footfall pattern, we combined the inter-limb coupling and the duty cycle of the stance phase, thus identifying several types of gaits: lateral walk, trot, out-of-phase walk, rotary gallop, transverse gallop, hop, half-bound, and full-bound. Out-of-phase walk, trot, and full-bound were robust and appeared to function as attractor gaits (i.e., a state to which the network flows and stabilizes) at low, intermediate, and high speeds respectively. In contrast, lateral walk, hop, transverse gallop, rotary gallop, and half-bound were more transient and therefore considered transitional gaits (i.e., a labile state of the network from which it flows to the attractor state). Surprisingly, lateral walk was less frequently observed. Using graph analysis, we demonstrated that transitions between gaits were predictable, not random. In summary, the wild-type mouse exhibits a wider repertoire of locomotor gaits than expected. Future locomotor studies should benefit from this paradigm in assessing transgenic mice or wild-type mice with neurotraumatic injury or neurodegenerative disease affecting gait.

Preventive Home Visits for Older People: A Systematic Review.

RÉSUMÉ L'augmentation du nombre de personnes âgées présentant des incapacités et ayant des maladies chroniques entraîne une hausse des besoins en services de santé à domicile. Le nombre d'études et de revues systématiques traitant des approches préventives pour cette clientèle a proliféré, générant un besoin de synthèse des connaissances. Nous avons mené une revue systématique de revues systématiques évaluant l'effet des programmes de visite préventive pour les personnes âgées. Des 5 973 citations identifiées dans plus de 30 bases de données de littérature grise et scientifique, 10 articles répondaient à tous les critères d'inclusion. Les revues systématiques étaient retenues si elles comprenaient des essais randomisés contrôlés comparant des interventions de soins à domicile offerts par un professionnel de la santé et ceux sans professionnels. Les interventions sont souvent des évaluations gériatriques globales et s'accompagnent de visites de suivi. Il ressort que les visites préventives multidimensionnelles à domicile ont le potentiel de diminuer la mortalité, en particulier chez les personnes âgées plus jeunes, et offrent aussi un potentiel d'amélioration de l'autonomie fonctionnelle. Toutefois, ces résultats doivent être interprétés avec prudence vue la diversité des interventions analysées.

Treatment refusal among patients with psoriasis.

BACKGROUND: Treatment refusal, which is defined as a patient actively refusing to take treatment despite physician recommendations, has never been evaluated in psoriasis. OBJECTIVE: To investigate refusal of topical treatments by patients living with psoriasis in France. METHODS: Using responses to an internet study, participants who refused topical treatment (n = 50) were compared to those who applied topical treatment (n = 205). Participants undergoing phototherapy, biotherapy, and oral treatment were excluded. Spearman rank correlations completed by Fisher's exact tests and Student's t-tests were performed. RESULTS: Comorbidities, localization of lesions, and symptoms associated with psoriasis were not significant predictors of treatment refusal. Compared to patients who accepted treatment, more patients who refused treatment believed that psoriasis is not manageable (80.0% versus 61.5%; p = 0.01), that psoriasis treatments never work (58.0% versus 27.5%; OR: 2.09 p < 0.0001), and that all creams have the same effects (54.0% versus 31.7%; OR: 1.7, p = 0.003). Among patients who reported seeking medical attention from physicians, more patients in the treatment refusal group reported some level of dissatisfaction with their relationship with their physician than in the treatment acceptance group. LIMITATIONS: The validity of the self-reported treatment refusal could not be evaluated. CONCLUSION: Treatment refusal is an important element to be taken into consideration in the management of psoriasis.

Mast cells can regulate skeletal muscle cell proliferation by multiple mechanisms.

INTRODUCTION: Mast cells (MCs) can stimulate cell proliferation, but their specific contribution to skeletal muscle regeneration is not well defined. METHODS: L6 myoblast proliferation was assessed in coculture with MCs or when grown with MC-conditioned media. To address the in vivo implication of MCs in regeneration, rats were treated with cromolyn, and myoblast proliferation, immune cell accumulation, and myogenic factors were assessed in bupivacaine-injured muscles. RESULTS: In vitro, both procedures increased the L6 cell proliferation rate, and this was tryptase-dependent. In vivo, MC stabilization increased myoblast proliferation and accumulation of macrophages CD68 and CD163 after injury. This correlated with a sequential increase in MyoD and myogenin protein level expression. CONCLUSIONS: MCs can directly stimulate muscle cell proliferation via tryptase. MCs can influence myoblast proliferation in vivo, but this effect seems to be predominantly related to their modulation of macrophage recruitment. The MC is a potential actor in the early stages of muscle healing.