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"Muscular Diseases - therapy"
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Beyond the Definitions of the Phenotypic Complications of Sickle Cell Disease : An Update on Management
The sickle hemoglobin is an abnormal hemoglobin due to point mutation (GAG → GTG) in exon 1 of the β globin gene resulting in the substitution of glutamic acid by valine at position 6 of the β globin polypeptide chain. Although the molecular lesion is a single-point mutation, the sickle gene is pleiotropic in nature causing multiple phenotypic expressions that constitute the various complications of sickle cell disease in general and sickle cell anemia in particular. The disease itself is chronic in nature but many of its complications are acute such as the recurrent acute painful crises (its hallmark), acute chest syndrome, and priapism. These complications vary considerably among patients, in the same patient with time, among countries and with age and sex. To date, there is no well-established consensus among providers on the management of the complications of sickle cell disease due in part to lack of evidence and in part to differences in the experience of providers. It is the aim of this paper to review available current approaches to manage the major complications of sickle cell disease. We hope that this will establish another preliminary forum among providers that may eventually lead the way to better outcomes.Erratum to “Beyond the Definitions of the Phenotypic Complications of Sickle Cell Disease: An Update on Management”dx.doi.org/10.1155/2013/861251
Journal Article
A pilot study of the eccentric decline squat in the management of painful chronic patellar tendinopathy
Objectives: This non-randomised pilot study investigated the effect of eccentric quadriceps training on 17 patients (22 tendons) with painful chronic patellar tendinopathy. Methods: Two different eccentric exercise regimens were used by subjects with a long duration of pain with activity (more than six months). (a) Nine consecutive patients (10 tendons; eight men, one woman; mean age 22 years) performed eccentric exercise with the ankle joint in a standard (foot flat) position. (b) Eight patients (12 tendons; five men, three women; mean age 28 years) performed eccentric training standing on a 25° decline board, designed to increase load on the knee extensor mechanism. The eccentric training was performed twice daily, with three sets of 15 repetitions, for 12 weeks. Primary outcome measures were (a) 100 mm visual analogue scale (VAS), where the subject recorded the amount of pain during activity, and (b) return to previous activity. Follow up was at 12 weeks, with a further limited follow up at 15 months. Results: Good clinical results were obtained in the group who trained on the decline board, with six patients (nine tendons) returning to sport and showing a significantly reduced amount of pain over the 12 week period. Mean VAS scores fell from 74.2 to 28.5 (p = 0.004). At 15 months, four patients (five tendons) reported satisfactory results (mean VAS 26.2). In the standard squat group the results were poor, with only one athlete returning to previous activity. Mean VAS scores in this group were 79.0 at baseline and 72.3 at 12 weeks (p = 0.144). Conclusion: In a small group of patients with patellar tendinopathy, eccentric squats on a decline board produced encouraging results in terms of pain reduction and return to function in the short term. Eccentric exercise using standard single leg squats in a similar sized group appeared to be a less effective form of rehabilitation in reducing pain and returning subjects to previous levels of activity.
Journal Article
Statin-Associated Myopathy: Emphasis on Mechanisms and Targeted Therapy
Hyperlipidemia is a major risk factor for cardiovascular morbidity and mortality. Statins are the first-choice therapy for dyslipidemias and are considered the cornerstone of atherosclerotic cardiovascular disease (ASCVD) in both primary and secondary prevention. Despite the statin-therapy-mediated positive effects on cardiovascular events, patient compliance is often poor. Statin-associated muscle symptoms (SAMS) are the most common side effect associated with treatment discontinuation. SAMS, which range from mild-to-moderate muscle pain, weakness, or fatigue to potentially life-threatening rhabdomyolysis, are reported by 10% to 25% of patients receiving statin therapy. There are many risk factors associated with patient features and hypolipidemic agents that seem to increase the risk of developing SAMS. Due to the lack of a “gold standard”, the diagnostic test for SAMS is based on a clinical criteria score, which is independent of creatine kinase (CK) elevation. Mechanisms that underlie the pathogenesis of SAMS remain almost unclear, though a high number of risk factors may increase the probability of myotoxicity induced by statin therapy. Some of these, related to pharmacokinetic properties of statins and to concomitant therapies or patient characteristics, may affect statin bioavailability and increase vulnerability to high-dose statins.
Journal Article
Exercise enhances skeletal muscle regeneration by promoting senescence in fibro-adipogenic progenitors
Idiopathic inflammatory myopathies cause progressive muscle weakness and degeneration. Since high-dose glucocorticoids might not lead to full recovery of muscle function, physical exercise is also an important intervention, but some exercises exacerbate chronic inflammation and muscle fibrosis. It is unknown how physical exercise can have both beneficial and detrimental effects in chronic myopathy. Here we show that senescence of fibro-adipogenic progenitors (FAPs) in response to exercise-induced muscle damage is needed to establish a state of regenerative inflammation that induces muscle regeneration. In chronic inflammatory myopathy model mice, exercise does not promote FAP senescence or resistance against tumor necrosis factor–mediated apoptosis. Pro-senescent intervention combining exercise and pharmacological AMPK activation reverses FAP apoptosis resistance and improves muscle function and regeneration. Our results demonstrate that the absence of FAP senescence after exercise leads to muscle degeneration with FAP accumulation. FAP-targeted pro-senescent interventions with exercise and pharmacological AMPK activation may constitute a therapeutic strategy for chronic inflammatory myopathy.
Some exercises exacerbate chronic inflammation and muscle fibrosis in chronic myopathy. Here, the authors show that senescence of fibro-adipogenic progenitors (FAPs) in response to exercise induces muscle regeneration, and impaired FAP senescence worsens inflammation and fibrosis in chronic myopathy in mice.
Journal Article
Perspectives on skeletal muscle stem cells
Skeletal muscle has remarkable regeneration capabilities, mainly due to its resident muscle stem cells (MuSCs). In this review, we introduce recently developed technologies and the mechanistic insights they provide to the understanding of MuSC biology, including the re-definition of quiescence and G
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states. Additionally, we present recent studies that link MuSC function with cellular heterogeneity, highlighting the complex regulation of self-renewal in regeneration, muscle disorders and aging. Finally, we discuss MuSC metabolism and its role, as well as the multifaceted regulation of MuSCs by their niche. The presented conceptual advances in the MuSC field impact on our general understanding of stem cells and their therapeutic use in regenerative medicine.
Skeletal muscle has a remarkable regenerative capacity, which can largely be attributed to resident muscle stem cells (MuSCs). Here, the authors review the molecular mechanisms regulating MuSC quiescence, activation and proliferation, how these processes are regulated by the stem cell niche, and the role of MuSCs in neuromuscular diseases.
Journal Article
Integrative Approaches to Myopathies and Muscular Dystrophies: Molecular Mechanisms, Diagnostics, and Future Therapies
Myopathies and muscular dystrophies are a diverse group of rare or ultra-rare diseases that significantly impact patients’ quality of life and pose major challenges for diagnosis and treatment. Despite their heterogeneity, many share common molecular mechanisms, particularly involving sarcomeric dysfunction, impaired autophagy, and disrupted gene expression. This review explores the genetic and pathophysiological foundations of major myopathy subtypes, including cardiomyopathies, metabolic and mitochondrial myopathies, congenital and distal myopathies, myofibrillar myopathies, inflammatory myopathies, and muscular dystrophies. Special emphasis is placed on the role of autophagy dysregulation in disease progression, as well as its therapeutic potential. We discuss emerging diagnostic approaches, such as whole-exome sequencing, advanced imaging, and muscle biopsy, alongside therapeutic strategies, including physiotherapy, supplementation, autophagy modulators, and gene therapies. Gene therapy methods, such as adeno-associated virus (AAV) vectors, CRISPR-Cas9, and antisense oligonucleotide, are evaluated for their promise and limitations. The review also highlights the potential of drug repurposing and artificial intelligence tools in advancing diagnostics and personalized treatment. By identifying shared molecular targets, particularly in autophagy and proteostasis networks, we propose unified therapeutic strategies across multiple myopathy subtypes. Finally, we discuss international research collaborations and rare disease programs that are driving innovation in this evolving field.
Journal Article
Critical illness polyneuropathy and myopathy: a major cause of muscle weakness and paralysis
Critical illness polyneuropathy (CIP) and myopathy (CIM) are complications of critical illness that present with muscle weakness and failure to wean from the ventilator. In addition to prolonging mechanical ventilation and hospitalisation, CIP and CIM increase hospital mortality in patients who are critically ill and cause chronic disability in survivors of critical illness. Structural changes associated with CIP and CIM include axonal nerve degeneration, muscle myosin loss, and muscle necrosis. Functional changes can cause electrical inexcitability of nerves and muscles with reversible muscle weakness. Microvascular changes and cytopathic hypoxia might disrupt energy supply and use. An acquired sodium channelopathy causing reduced muscle membrane and nerve excitability is a possible unifying mechanism underlying CIP and CIM. The diagnosis of CIP, CIM, or combined CIP and CIM relies on clinical, electrophysiological, and muscle biopsy investigations. Control of hyperglycaemia might reduce the severity of these complications of critical illness, and early rehabilitation in the intensive care unit might improve the functional recovery and independence of patients.
Journal Article
GNE Myopathy: Etiology, Diagnosis, and Therapeutic Challenges
GNE myopathy, previously known as hereditary inclusion body myopathy (HIBM), or Nonaka myopathy, is a rare autosomal recessive muscle disease characterized by progressive skeletal muscle atrophy. It has an estimated prevalence of 1 to 9:1,000,000. GNE myopathy is caused by mutations in the GNE gene which encodes the rate-limiting enzyme of sialic acid biosynthesis. The pathophysiology of the disease is not entirely understood, but hyposialylation of muscle glycans is thought to play an essential role. The typical presentation is bilateral foot drop caused by weakness of the anterior tibialis muscles with onset in early adulthood. The disease slowly progresses over the next decades to involve skeletal muscles throughout the body, with relative sparing of the quadriceps until late stages of the disease. The diagnosis of GNE myopathy should be considered in young adults presenting with bilateral foot drop. Histopathologic findings on muscle biopsies include fiber size variation, atrophic fibers, lack of inflammation, and the characteristic “rimmed” vacuoles on modified Gomori trichome staining. The diagnosis is confirmed by the presence of pathogenic (mostly missense) mutations in both alleles of the GNE gene. Although there is no approved therapy for this disease, preclinical and clinical studies of several potential therapies are underway, including substrate replacement and gene therapy-based strategies. However, developing therapies for GNE myopathy is complicated by several factors, including the rare incidence of disease, limited preclinical models, lack of reliable biomarkers, and slow disease progression.
Journal Article
Effects and moderators of exercise on muscle strength, muscle function and aerobic fitness in patients with cancer: a meta-analysis of individual patient data
ObjectiveTo optimally target exercise interventions for patients with cancer, it is important to identify which patients benefit from which interventions.DesignWe conducted an individual patient data meta-analysis to investigate demographic, clinical, intervention-related and exercise-related moderators of exercise intervention effects on physical fitness in patients with cancer.Data sourcesWe identified relevant studies via systematic searches in electronic databases (PubMed, Embase, PsycINFO and CINAHL).Eligibility criteriaWe analysed data from 28 randomised controlled trials investigating the effects of exercise on upper body muscle strength (UBMS) and lower body muscle strength (LBMS), lower body muscle function (LBMF) and aerobic fitness in adult patients with cancer.ResultsExercise significantly improved UBMS (β=0.20, 95% Confidence Interval (CI) 0.14 to 0.26), LBMS (β=0.29, 95% CI 0.23 to 0.35), LBMF (β=0.16, 95% CI 0.08 to 0.24) and aerobic fitness (β=0.28, 95% CI 0.23 to 0.34), with larger effects for supervised interventions. Exercise effects on UBMS were larger during treatment, when supervised interventions included ≥3 sessions per week, when resistance exercises were included and when session duration was >60 min. Exercise effects on LBMS were larger for patients who were living alone, for supervised interventions including resistance exercise and when session duration was >60 min. Exercise effects on aerobic fitness were larger for younger patients and when supervised interventions included aerobic exercise.ConclusionExercise interventions during and following cancer treatment had small effects on UBMS, LBMS, LBMF and aerobic fitness. Demographic, intervention-related and exercise-related characteristics including age, marital status, intervention timing, delivery mode and frequency and type and time of exercise sessions moderated the exercise effect on UBMS, LBMS and aerobic fitness.
Journal Article