Concept: Neuromuscular disease
It is widely believed that an active cool-down is more effective for promoting post-exercise recovery than a passive cool-down involving no activity. However, research on this topic has never been synthesized and it therefore remains largely unknown whether this belief is correct. This review compares the effects of various types of active cool-downs with passive cool-downs on sports performance, injuries, long-term adaptive responses, and psychophysiological markers of post-exercise recovery. An active cool-down is largely ineffective with respect to enhancing same-day and next-day(s) sports performance, but some beneficial effects on next-day(s) performance have been reported. Active cool-downs do not appear to prevent injuries, and preliminary evidence suggests that performing an active cool-down on a regular basis does not attenuate the long-term adaptive response. Active cool-downs accelerate recovery of lactate in blood, but not necessarily in muscle tissue. Performing active cool-downs may partially prevent immune system depression and promote faster recovery of the cardiovascular and respiratory systems. However, it is unknown whether this reduces the likelihood of post-exercise illnesses, syncope, and cardiovascular complications. Most evidence indicates that active cool-downs do not significantly reduce muscle soreness, or improve the recovery of indirect markers of muscle damage, neuromuscular contractile properties, musculotendinous stiffness, range of motion, systemic hormonal concentrations, or measures of psychological recovery. It can also interfere with muscle glycogen resynthesis. In summary, based on the empirical evidence currently available, active cool-downs are largely ineffective for improving most psychophysiological markers of post-exercise recovery, but may nevertheless offer some benefits compared with a passive cool-down.
Skeletal muscle is a plastic organ that is maintained by multiple pathways regulating cell and protein turnover. During muscle atrophy, proteolytic systems are activated, and contractile proteins and organelles are removed, resulting in the shrinkage of muscle fibers. Excessive loss of muscle mass is associated with poor prognosis in several diseases, including myopathies and muscular dystrophies, as well as in systemic disorders such as cancer, diabetes, sepsis and heart failure. Muscle loss also occurs during aging. In this paper, we review the key mechanisms that regulate the turnover of contractile proteins and organelles in muscle tissue, and discuss how impairments in these mechanisms can contribute to muscle atrophy. We also discuss how protein synthesis and degradation are coordinately regulated by signaling pathways that are influenced by mechanical stress, physical activity, and the availability of nutrients and growth factors. Understanding how these pathways regulate muscle mass will provide new therapeutic targets for the prevention and treatment of muscle atrophy in metabolic and neuromuscular diseases.
Gene replacement therapies utilizing adeno-associated viral (AAV) vectors hold great promise for treating Duchenne muscular dystrophy (DMD). A related approach uses AAV vectors to edit specific regions of the DMD gene using CRISPR/Cas9. Here we develop multiple approaches for editing the mutation in dystrophic mdx(4cv) mice using single and dual AAV vector delivery of a muscle-specific Cas9 cassette together with single-guide RNA cassettes and, in one approach, a dystrophin homology region to fully correct the mutation. Muscle-restricted Cas9 expression enables direct editing of the mutation, multi-exon deletion or complete gene correction via homologous recombination in myogenic cells. Treated muscles express dystrophin in up to 70% of the myogenic area and increased force generation following intramuscular delivery. Furthermore, systemic administration of the vectors results in widespread expression of dystrophin in both skeletal and cardiac muscles. Our results demonstrate that AAV-mediated muscle-specific gene editing has significant potential for therapy of neuromuscular disorders.
Centronuclear myopathies (CNM) are non-dystrophic muscle diseases for which no effective therapy is currently available. The most severe form, X-linked CNM, is caused by myotubularin 1 (MTM1) loss-of-function mutations, while the main autosomal dominant form is due to dynamin2 (DNM2) mutations. We previously showed that genetic reduction of DNM2 expression in Mtm1 knockout (Mtm1KO) mice prevents development of muscle pathology. Here we show that systemic delivery of Dnm2 antisense oligonucleotides (ASOs) into Mtm1KO mice efficiently reduces DNM2 protein level in muscle and prevents the myopathy from developing. Moreover, systemic ASO injection into severely affected mice leads to reversal of muscle pathology within 2 weeks. Thus, ASO-mediated DNM2 knockdown can efficiently correct muscle defects due to loss of MTM1, providing an attractive therapeutic strategy for this disease.
A substantial number of patients admitted to the ICU because of an acute illness, complicated surgery, severe trauma, or burn injury will develop a de novo form of muscle weakness during the ICU stay that is referred to as “intensive care unit acquired weakness” (ICUAW). This ICUAW evoked by critical illness can be due to axonal neuropathy, primary myopathy, or both. Underlying pathophysiological mechanisms comprise microvascular, electrical, metabolic, and bioenergetic alterations, interacting in a complex way and culminating in loss of muscle strength and/or muscle atrophy. ICUAW is typically symmetrical and affects predominantly proximal limb muscles and respiratory muscles, whereas facial and ocular muscles are often spared. The main risk factors for ICUAW include high severity of illness upon admission, sepsis, multiple organ failure, prolonged immobilization, and hyperglycemia, and also older patients have a higher risk. The role of corticosteroids and neuromuscular blocking agents remains unclear. ICUAW is diagnosed in awake and cooperative patients by bedside manual testing of muscle strength and the severity is scored by the Medical Research Council sum score. In cases of atypical clinical presentation or evolution, additional electrophysiological testing may be required for differential diagnosis. The cornerstones of prevention are aggressive treatment of sepsis, early mobilization, preventing hyperglycemia with insulin, and avoiding the use parenteral nutrition during the first week of critical illness. Weak patients clearly have worse acute outcomes and consume more healthcare resources. Recovery usually occurs within weeks or months, although it may be incomplete with weakness persisting up to 2 years after ICU discharge. Prognosis appears compromised when the cause of ICUAW involves critical illness polyneuropathy, whereas isolated critical illness myopathy may have a better prognosis. In addition, ICUAW has shown to contribute to the risk of 1-year mortality. Future research should focus on new preventive and/or therapeutic strategies for this detrimental complication of critical illness and on clarifying how ICUAW contributes to poor longer-term prognosis.
- Physical medicine and rehabilitation clinics of North America
- Published over 4 years ago
Iliotibial band syndrome (ITBS) has known biomechanical factors with an unclear explanation based on only strength and flexibility deficits. Neuromuscular coordination has emerged as a likely reason for kinematic faults guiding research toward motor control. This article discusses ITBS in relation to muscle performance factors, fascial considerations, epidemiology, functional anatomy, strength deficits, kinematics, iliotibial strain and strain rate, and biomechanical considerations. Evidence-based exercise approaches are reviewed for ITBS, including related methods used to train the posterior hip muscles.
Effective stabilization is important to increase sports performance. Imbalanced spinal muscle responses between the left and right sides increase the risk of spinal buckling and microtrauma at the intervertebral joints. The purpose of this study was to confirm whether intensive unilateral neuromuscular training (IUNT) focusing on the non-dominant side of the low back improves balanced muscle responses and spinal stability. The IUNT group (n = 8) performed side bridge and quadruped exercises using their non-dominant trunk muscles for 8 weeks, while the control group (n = 8) performed their regular training. Before and after the training, motion-capture cameras measured trunk angular displacement, and electromyography recorded the activities of both multifidus muscles (L4-5) during unexpected sudden forward perturbation. After the training in the IUNT group, the difference in onset time between both sides decreased to approximately 120 % compared with that before the training. The asymmetry of muscle activities also decreased from 56 to 23 %. Moreover, the angular displacement on the sagittal plane decreased to approximately 35 % after the training. We expect that IUNT focused on the non-dominant side of the low back will be useful to improve balanced back muscle responses and spinal stability during sudden trunk perturbation.
Dendritic cells (DC) have been reported among inflammatory infiltrating cells in muscle tissue in idiopathic inflammatory myopathies (IIM), but to our knowledge no studies concerning the expression of langerin (CD207) or fascin (markers of immature and mature DC, respectively) in IIM have been published.
Fatigue induced via a maximal isometric contraction of a single limb muscle group can evoke a “cross-over” of fatigue that reduces voluntary muscle activation and maximum isometric force in the rested contralateral homologous muscle group. We asked whether a cross-over of fatigue also occurs when fatigue is induced via high-intensity endurance exercise involving a substantial muscle mass. Specifically, we used high-intensity single-leg cycling to induce fatigue and evaluated associated effects on maximum cycling power (P (max)) in the fatigued ipsilateral leg (FAT(leg)) as well as the rested contralateral leg (REST(leg)). On separate days, 12 trained cyclists performed right leg P (max) trials before and again 30 s, 3, 5, and 10 min after a cycling time trial (TT, 10 min) performed either with their right or left leg. Fatigue was estimated by comparing exercise-induced changes in P (max) and maximum handgrip isometric force (F (max)). Mean power produced during the right and left leg TTs did not differ (203 ± 8 vs. 199 ± 8 W). Compared to pre-TT, FAT(leg) P (max) was reduced by 22 ± 3 % at 30 s post-TT and remained reduced by 9 ± 2 % at 5 min post-TT (both P < 0.05). Despite considerable power loss in the FAT(leg), post-TT REST(leg) P (max) (596-603 W) did not differ from pre-TT values (596 ± 35 W). There were no alterations in handgrip F (max) (529-547 N). Our data suggest that any potential cross-over of fatigue, if present at all, was not sufficient to measurably compromise REST(leg) P (max) in trained cyclists. These results along with the lack of changes in handgrip F (max) indicate that impairments in maximal voluntary neuromuscular function were specific to working muscles.
Autophagy is a vesicular trafficking pathway that regulates the degradation of aggregated proteins and damaged organelles. Initiation of autophagy requires several multiprotein signaling complexes, such as the ULK1 kinase complex and the Vps34 lipid kinase complex, which generates phosphatidylinositol 3-phosphate [PtdIns(3)P] on the forming autophagosomal membrane. Alterations in autophagy have been reported for various diseases, including myopathies. Here we show that skeletal muscle autophagy is compromised in mice deficient in the X-linked myotubular myopathy (XLMTM)-associated PtdIns(3)P phosphatase myotubularin (MTM1). Mtm1-deficient muscle displays several cellular abnormalities, including a profound increase in ubiquitin aggregates and abnormal mitochondria. Further, we show that Mtm1 deficiency is accompanied by activation of mTORC1 signaling, which persists even following starvation. In vivo pharmacological inhibition of mTOR is sufficient to normalize aberrant autophagy and improve muscle phenotypes in Mtm1 null mice. These results suggest that aberrant mTORC1 signaling and impaired autophagy are consequences of the loss of Mtm1 and may play a primary role in disease pathogenesis.