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Rodent studies investigating long‐term effects following termination of hypertrophy‐inducing loading have predominantly involved exposures such as synergist ablation and weighted wheel running or ladder climbing. This research yielded a spectrum of results regarding the extent of detraining in terms of muscle mass and myonuclei number. The studies were also limited in their lack of sensitive performance measures and indirect relatedness to resistance training. Our research group developed and validated a relevant rat model of resistance‐type training that induces increased muscle mass and performance. The aim of the present study was to determine to what extent these features persist 3 months following the termination of this training. While performance returned to baseline, muscle mass remained elevated by 17% and a shift in distribution to larger muscle fibers persisted. A 16% greater total RNA and heightened mRNA levels of ribosomal protein S6 kinases implicated preserved transcriptional output and ribosomal content. Remodeling of muscle fiber nuclei was consistent with these findings – increased nuclear number and a distribution shift to a more circular nuclear shape. These findings indicate that muscle mass detrains at a slower rate than performance and implicates multiple forms of myonuclear remodeling in muscle memory. The purpose of the present study was to determine the extent of detraining in a relevant rat model of resistance‐type training. By 3 months following training cessation, performance returned to baseline while muscle mass and transcriptional output was heightened. This was accompanied by alterations in nuclei number and shape thereby supporting the concept of long‐term myonuclear remodeling as a contributor in muscle mass regulation and muscle memory.

The Snell dwarf mouse (Pit1dw/dw), an animal model of congenital combined pituitary hormone deficiency, displays skeletal muscle weakness. While enhanced responsivity to repeated exposures of muscle contractions have been documented for Snell dwarf mice, the response following single exposure to distinct contraction protocols remained uncharacterized. The purpose of this study was to investigate the muscle recovery of Snell dwarf and control littermate mice following a single exposure to two separate protocols—an intermittent slow velocity (30°/s) contraction protocol or a continuous rapid velocity (500°/s) contraction protocol. Following both protocols for control mice, torque values were 30% and 80% of pre‐protocol values at 5 min and 3 days, respectively. At 10 days, performance returned to baseline for the 30°/s protocol and were depressed for the 500°/s protocol. For Snell dwarf mice following both protocols, torques were depressed to 5% of pre‐protocol values at 5 min and returned to baseline by 3 days. Recovery following the 30°/s protocol for control mice and both protocols for Snell dwarf mice coincided with increased transcriptional output, upregulation of cytokine‐mediated signaling genes, and a distribution shift to smaller muscle fibers with reduced area per nucleus. These features represent efficacious remodeling ubiquitous across distinct contraction paradigms in the context of the Pit1 mutation.

Signalling muscle fatigue Many neuromuscular conditions, such as Duchenne muscular dystrophy, involve an exaggerated exercise-induced fatigue response. Experiments in mice have identified a potential cause of this fatigue: when neuronal nitric oxide synthase (nNOS) is missing from its normal location on the muscle membrane, the blood vessels that supply the muscles fail to relax normally and the animals experience post-exercise fatigue. Sarcolemmal nNOS was found to be reduced in biopsies from patients with a range of distinct myopathies pointing towards a common mechanism of fatigue. These results suggest that patients with an exaggerated fatigue response to mild exercise may respond to treatment that improves exercise-induced signalling. Many neuromuscular conditions are characterized by an exaggerated exercise-induced fatigue response. This form of inactivity is a major determinant of disability. The mechanism underlying this type of fatigue remains unknown. It is shown in mice that such exaggerated fatigue is due to a lack of contraction-induced signalling from sarcolemma-localized nNOS. In addition, in patient biopsies from a large number of distinct myopathies, sarcolemmal nNOS is reduced—pointing towards a common mechanism of fatigue. Many neuromuscular conditions are characterized by an exaggerated exercise-induced fatigue response that is disproportionate to activity level. This fatigue is not necessarily correlated with greater central or peripheral fatigue in patients 1 , and some patients experience severe fatigue without any demonstrable somatic disease 2 . Except in myopathies that are due to specific metabolic defects, the mechanism underlying this type of fatigue remains unknown 2 . With no treatment available, this form of inactivity is a major determinant of disability 3 . Here we show, using mouse models, that this exaggerated fatigue response is distinct from a loss in specific force production by muscle, and that sarcolemma-localized signalling by neuronal nitric oxide synthase (nNOS) in skeletal muscle is required to maintain activity after mild exercise. We show that nNOS -null mice do not have muscle pathology and have no loss of muscle-specific force after exercise but do display this exaggerated fatigue response to mild exercise. In mouse models of nNOS mislocalization from the sarcolemma, prolonged inactivity was only relieved by pharmacologically enhancing the cGMP signal that results from muscle nNOS activation during the nitric oxide signalling response to mild exercise. Our findings suggest that the mechanism underlying the exaggerated fatigue response to mild exercise is a lack of contraction-induced signalling from sarcolemma-localized nNOS, which decreases cGMP-mediated vasomodulation in the vessels that supply active muscle after mild exercise. Sarcolemmal nNOS staining was decreased in patient biopsies from a large number of distinct myopathies, suggesting a common mechanism of fatigue. Our results suggest that patients with an exaggerated fatigue response to mild exercise would show clinical improvement in response to treatment strategies aimed at improving exercise-induced signalling.

Dystroglycan (DG) is a highly expressed extracellular matrix receptor that is linked to the cytoskeleton in skeletal muscle. DG is critical for the function of skeletal muscle, and muscle with primary defects in the expression and/or function of DG throughout development has many pathological features and a severe muscular dystrophy phenotype. In addition, reduction in DG at the sarcolemma is a common feature inmuscle biopsies from patients with various types of muscular dystrophy. However, the consequence of disrupting DG in mature muscle is not known. Here, we investigated muscles of transgenic mice several months after genetic knockdown of DG at maturity. In our study, an increase in susceptibility to contraction-induced injury was the first pathological feature observed after the levels of DG at the sarcolemma were reduced. The contraction-induced injury was not accompanied by increased necrosis, excitation–contraction uncoupling, or fragility of the sarcolemma. Rather, disruption of the sarcomeric cytoskeleton was evident as reduced passive tension and decreased titin immunostaining. These results reveal a role for DG in maintaining the stability of the sarcomeric cytoskeleton during contraction and provide mechanistic insight into the cause of the reduction in strength that occurs in muscular dystrophy after lengthening contractions.

Skeletal muscle basal lamina is linked to the sarcolemma through transmembrane receptors, including integrins and dystroglycan. The function of dystroglycan relies critically on posttranslational glycosylation, a common target shared by a genetically heterogeneous group of muscular dystrophies characterized by α-dystroglycan hypoglycosylation. Here we show that both dystroglycan and integrin α7 contribute to force-production of muscles, but that only disruption of dystroglycan causes detachment of the basal lamina from the sarcolemma and renders muscle prone to contraction-induced injury. These phenotypes of dystroglycan-null muscles are recapitulated by Largemyd muscles, which have an intact dystrophin-glycoprotein complex and lack only the laminin globular domain-binding motif on α-dystroglycan. Compromised sarcolemmal integrity is directly shown in Largemyd muscles and similarly in normal muscles when arenaviruses compete with matrix proteins for binding α-dystroglycan. These data provide direct mechanistic insight into how the dystroglycan-linked basal lamina contributes to the maintenance of sarcolemmal integrity and protects muscles from damage.

Mutations in the dysferlin gene underlie a group of autosomal recessive muscle-wasting disorders denoted as dysferlinopathies. Dysferlin has been shown to play roles in muscle membrane repair and muscle regeneration, both of which require vesicle-membrane fusion. However, the mechanism by which muscle becomes dystrophic in these disorders remains poorly understood. Although muscle inflammation is widely recognized in dysferlinopathy and dysferlin is expressed in immune cells, the contribution of the immune system to the pathology of dysferlinopathy remains to be fully explored. Here, we show that the complement system plays an important role in muscle pathology in dysferlinopathy. Dysferlin deficiency led to increased expression of complement factors in muscle, while muscle-specific transgenic expression of dysferlin normalized the expression of complement factors and eliminated the dystrophic phenotype present in dysferlin-null mice. Furthermore, genetic disruption of the central component (C3) of the complement system ameliorated muscle pathology in dysferlin-deficient mice but had no significant beneficial effect in a genetically distinct model of muscular dystrophy, mdx mice. These results demonstrate that complement-mediated muscle injury is central to the pathogenesis of dysferlinopathy and suggest that targeting the complement system might serve as a therapeutic approach for this disease.

Background The vast majority of dynamometer-based animal models for investigation of the response to chronic muscle contraction exposure has been limited to analysis of isometric, lengthening, or shortening contractions in isolation. An exception to this has been the utilization of a rat model to study stretch-shortening contractions (SSCs), a sequence of consecutive isometric, lengthening, and shortening contractions common during daily activity and resistance-type exercise. However, the availability of diverse genetic strains of rats is limited. Therefore, the purpose of the present study was to develop a dynamometer-based SSC training protocol to induce increased muscle mass and performance in plantarflexor muscles of mice. Methods Young (3 months old) C57BL/6 mice were subjected to 1 month of plantarflexion SSC training. Hindlimb muscles were analyzed for muscle mass, quantitative morphology, myogenesis/myopathy relevant gene expression, and fiber type distribution. Results The main aim of the research was achieved when training induced a 2-fold increase in plantarflexion peak torque output and a 19% increase in muscle mass for the agonist plantaris (PLT) muscle. In establishing this model, several outcomes emerged which raised the value of the model past that of being a mere recapitulation of the rat model. An increase in the number of muscle fibers per transverse muscle section accounted for the PLT muscle mass gain while the antagonist tibialis anterior (TA) muscle atrophied by 30% with preferential atrophy of type IIb and IIx fibers. These alterations were accompanied by distinct gene expression profiles. Conclusions The findings confirm the development of a stretch-shortening contraction training model for the PLT muscle of mice and demonstrate that increased cross-sectional fiber number can occur following high-intensity SSC training. Furthermore, the TA muscle atrophy provides direct evidence for the concept of muscle imbalance in phasic non-weight bearing muscles, a concept largely characterized based on clinical observation of patients. The susceptibility to this imbalance is demonstrated to be selective for the type IIb and IIx muscle fiber types. Overall, the study highlights the importance of considering muscle fiber number modulation and the effect of training on surrounding muscles in exercise comprised of SSCs.

Investigation of volitional animal models of resistance training has been instrumental in our understanding of adaptive training. However, these studies have lacked reactive force measurements, a precise performance measure, and morphological analysis at a distinct phase of training - when initial strength gains precede muscle hypertrophy. Our aim was to expose rats to one month of training (70 or 700 g load) on a custom-designed weight-lifting apparatus for analysis of reactive forces and muscle morphology prior to muscle hypertrophy. Exclusively following 700 g load training, forces increased by 21% whereas muscle masses remained unaltered. For soleus (SOL) and tibialis anterior (TA) muscles, 700 g load training increased muscle fiber number per unit area by ~20% and decreased muscle fiber area by ~20%. Additionally, number of muscle fibers per section increased by 18% for SOL muscles. These results establish that distinct morphological alterations accompany early strength gains in a volitional animal model of load-dependent adaptive resistance training.

Objective: Despite cleft palate repair, velopharyngeal competence is not achieved in ∼15% of patients, often necessitating secondary surgical correction. Velopharyngeal competence postrepair may require the conversion of levator veli palatini muscle fibers from injury-susceptible type 2 fibers to injury-resistant type 1 fibers. As an initial step to determining the validity of this theory, we tested the hypothesis that, in most cases, repair induces the transformation to type 1 fibers, thus diminishing susceptibility to injury. Interventions: Single permeabilized levator veli palatini muscle fibers were obtained from normal palates and nonrepaired congenitally-clefted palates of young (2 months old) and adult (14 to 15 months old) goats and from repaired palates of adult goats (8 months old). Repair was done at 2 months of age using a modified von Langenbeck technique. Main Outcome Measures: Fiber type was determined by contractile properties and susceptibility to injury was assessed by force deficit, the decrease in maximum force following a lengthening contraction protocol expressed as a percentage of initial force. Results: For normal palates and cleft palates of young goats, the majority of the fibers were type 2 with force deficits of ∼40%. Following repair, 80% of the fibers were type 1 with force deficits of 20% ± 2%; these deficits were 45% of those for nonrepaired cleft palates of adult goats (p < .0001). Conclusion: The decrease in the percentage of type 2 fibers and susceptibility to injury may be important for the development of a functional levator veli palatini muscle postrepair.

Objective: Levator veli palatini muscles from normal palates of adult humans and goats are predominantly slow oxidative (type 1) fibers. However, 85% of levator veli palatini fibers from cleft palates of adult goats are physiologically fast (type 2). This fiber composition difference between cleft and normal palates may have implications in palatal function. For limb muscles, type 2 muscle fibers are more susceptible to lengthening contraction-induced injury than are type 1 fibers. We tested the hypothesis that, compared with single permeabilized levator veli palatini muscle fibers from normal palates of adult goats, those from cleft palates are more susceptible to lengthening contraction-induced injury. Interventions: Congenital cleft palates were the result of chemically-induced decreased movement of the fetal head and tongue causing obstruction of palatal closure. Each muscle fiber was maximally activated and lengthened. Outcome Measures: Fiber type was determined by contractile properties and gel electrophoresis. Susceptibility to injury was assessed by measuring the decrease in maximum force following the lengthening contraction, expressed as a percentage of the initial force. Results: Compared with fibers from normal palates that were all type 1 and had force deficits of 23 ± 1%, fibers from cleft palates were all type 2 and sustained twofold greater deficits, 40 ± 1% (p = .001). Conclusion: Levator veli palatini muscles from cleft palates of goats contain predominantly type 2 fibers that are highly susceptible to lengthening contraction-induced injury. This finding may have implications regarding palatal function and the incidence of velopharyngeal incompetence.