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Comprehensive Physiology Sep 2018The immune response to acute muscle damage is important for normal repair. However, in chronic diseases such as many muscular dystrophies, the immune response can... (Review)
Review
The immune response to acute muscle damage is important for normal repair. However, in chronic diseases such as many muscular dystrophies, the immune response can amplify pathology and play a major role in determining disease severity. Muscular dystrophies are inheritable diseases that vary tremendously in severity, but share the progressive loss of muscle mass and function that can be debilitating and lethal. Mutations in diverse genes cause muscular dystrophy, including genes that encode proteins that maintain membrane strength, participate in membrane repair, or are components of the extracellular matrix or the nuclear envelope. In this article, we explore the hypothesis that an important feature of many muscular dystrophies is an immune response adapted to acute, infrequent muscle damage that is misapplied in the context of chronic injury. We discuss the involvement of the immune system in the most common muscular dystrophy, Duchenne muscular dystrophy, and show that the immune system influences muscle death and fibrosis as disease progresses. We then present information on immune cell function in other muscular dystrophies and show that for many muscular dystrophies, release of cytosolic proteins into the extracellular space may provide an initial signal, leading to an immune response that is typically dominated by macrophages, neutrophils, helper T-lymphocytes, and cytotoxic T-lymphocytes. Although those features are similar in many muscular dystrophies, each muscular dystrophy shows distinguishing features in the magnitude and type of inflammatory response. These differences indicate that there are disease-specific immunomodulatory molecules that determine response to muscle cell damage caused by diverse genetic mutations. © 2018 American Physiological Society. Compr Physiol 8:1313-1356, 2018.
Topics: Humans; Muscular Dystrophies, Limb-Girdle; Muscular Dystrophy, Duchenne; Muscular Dystrophy, Facioscapulohumeral
PubMed: 30215857
DOI: 10.1002/cphy.c170052 -
Muscle & Nerve Jun 2021
Topics: Female; Humans; Muscular Dystrophies; Muscular Dystrophies, Limb-Girdle; Pregnancy
PubMed: 33760246
DOI: 10.1002/mus.27242 -
Current Opinion in Neurology Oct 2018Muscle and bone are intrinsically linked, and therefore, it is not surprising that many muscular dystrophies are associated with impaired bone health and increased risk... (Review)
Review
PURPOSE OF REVIEW
Muscle and bone are intrinsically linked, and therefore, it is not surprising that many muscular dystrophies are associated with impaired bone health and increased risk of osteoporosis. Osteoporotic fracture is an important and preventable cause of morbidity and mortality. This article will firstly review the general causes of impaired bone health in muscular dystrophies and then focus on the evidence available for the diagnosis and treatment of osteoporosis in specific conditions.
RECENT FINDINGS
With the exception of DMD, there is a paucity of data regarding bone health in muscular dystrophies. However, it appears that in common with all types of muscular dystrophies that cause a significant level of muscle weakness and disability there is an increased risk of falls, fractures and decreased vitamin D levels. A better understanding of the extent of the impaired bone health and underlying causes could help to identify potential new therapeutic agents and aid clinical care.
SUMMARY
It would be prudent for clinicians to assess fracture risk in their muscular dystrophy patients and if appropriate, arrange surveillance and recommend vitamin D supplementation. Additionally, fracture should be considered in any patient presenting with new-onset bone pain.
Topics: Bone Diseases; Bone and Bones; Humans; Muscular Dystrophies; Osteoporotic Fractures; Risk Assessment
PubMed: 30080716
DOI: 10.1097/WCO.0000000000000603 -
Matrix Biology : Journal of the... Aug 2018The production of force and power are inherent properties of skeletal muscle, and regulated by contractile proteins within muscle fibers. However, skeletal muscle... (Review)
Review
The production of force and power are inherent properties of skeletal muscle, and regulated by contractile proteins within muscle fibers. However, skeletal muscle integrity and function also require strong connections between muscle fibers and their extracellular matrix (ECM). A well-organized and pliant ECM is integral to muscle function and the ability for many different cell populations to efficiently migrate through ECM is critical during growth and regeneration. For many neuromuscular diseases, genetic mutations cause disruption of these cytoskeletal-ECM connections, resulting in muscle fragility and chronic injury. Ultimately, these changes shift the balance from myogenic pathways toward fibrogenic pathways, culminating in the loss of muscle fibers and their replacement with fatty-fibrotic matrix. Hence a common pathological hallmark of muscular dystrophy is prominent fibrosis. This review will cover the salient features of muscular dystrophy pathogenesis, highlight the signals and cells that are important for myogenic and fibrogenic actions, and discuss how fibrosis alters the ECM of skeletal muscle, and the consequences of fibrosis in developing therapies.
Topics: Animals; Clinical Trials as Topic; Extracellular Matrix; Fibrosis; Humans; Muscle, Skeletal; Muscular Dystrophies; Signal Transduction
PubMed: 29408413
DOI: 10.1016/j.matbio.2018.01.014 -
Cells Aug 2023Tripartite motif-containing protein 32 (TRIM32) is a member of the tripartite motif family and is highly conserved from flies to humans. Via its E3 ubiquitin ligase... (Review)
Review
Tripartite motif-containing protein 32 (TRIM32) is a member of the tripartite motif family and is highly conserved from flies to humans. Via its E3 ubiquitin ligase activity, TRIM32 mediates and regulates many physiological and pathophysiological processes, such as growth, differentiation, muscle regeneration, immunity, and carcinogenesis. TRIM32 plays multifunctional roles in the maintenance of skeletal muscle. Genetic variations in the gene are associated with skeletal muscular dystrophies in humans, including limb-girdle muscular dystrophy type 2H (LGMD2H). LGMD2H-causing genetic variations of TRIM32 occur most frequently in the C-terminal NHL (ncl-1, HT2A, and lin-41) repeats of TRIM32. LGMD2H is characterized by skeletal muscle dystrophy, myopathy, and atrophy. Surprisingly, most patients with LGMD2H show minimal or no dysfunction in other tissues or organs, despite the broad expression of TRIM32 in various tissues. This suggests more prominent roles for TRIM32 in skeletal muscle than in other tissues or organs. This review is focused on understanding the physiological roles of TRIM32 in skeletal muscle, the pathophysiological mechanisms mediated by TRIM32 genetic variants in LGMD2H patients, and the correlations between TRIM32 and Duchenne muscular dystrophy (DMD).
Topics: Humans; Muscle, Skeletal; Muscular Dystrophies, Limb-Girdle; Muscular Dystrophy, Duchenne; Atrophy; Tripartite Motif Proteins; Transcription Factors; Ubiquitin-Protein Ligases
PubMed: 37626915
DOI: 10.3390/cells12162104 -
Clinica Chimica Acta; International... Aug 2019Titin, encoded by the gene TTN, is the largest human protein, and plays central roles in sarcomeric structures and functions in skeletal and cardiac muscles. Mutations... (Review)
Review
Titin, encoded by the gene TTN, is the largest human protein, and plays central roles in sarcomeric structures and functions in skeletal and cardiac muscles. Mutations of TTN are causally related to specific types of muscular dystrophies and cardiomyopathies. A developed methodology of next generation sequencing has recently led to the identification of novel TTN mutations in such diseases. The clinical significance of titin is now emerging as a target for genetic strategies. Titin-related muscular dystrophies include tibial muscular dystrophy, limb-girdle muscular dystrophy, Emery-Dreifuss muscular dystrophy, hereditary myopathy with early respiratory failure, central core myopathy, centronuclear myopathies, and Salih myopathy. Truncation mutations of TTN have been identified as the most frequent genetic cause of dilated cardiomyopathy. In this review article, we highlight the role of titin and impact of TTN mutations in the pathogenesis of muscular dystrophies and cardiomyopathies. Recently, a novel sensitive sandwich enzyme-linked immunosorbent assay (ELISA) for the detection of the urinary titin N-terminal fragments (U-TN) has been established. We discuss the clinical significance of U-TN in the diagnosis of muscular dystrophies and differential diagnosis of cardiomyopathies, as well as risk stratification in dilated cardiomyopathy.
Topics: Biomarkers; Cardiomyopathies; Connectin; Humans; Muscular Dystrophies; Mutation; Protein Isoforms
PubMed: 30959043
DOI: 10.1016/j.cca.2019.04.005 -
Journal of Neuromuscular Diseases 2021Glucocorticoid steroids are widely used as immunomodulatory agents in acute and chronic conditions. Glucocorticoid steroids such as prednisone and deflazacort are... (Review)
Review
Glucocorticoid steroids are widely used as immunomodulatory agents in acute and chronic conditions. Glucocorticoid steroids such as prednisone and deflazacort are recommended for treating Duchenne Muscular Dystrophy where their use prolongs ambulation and life expectancy. Despite this benefit, glucocorticoid use in Duchenne Muscular Dystrophy is also associated with significant adverse consequences including adrenal suppression, growth impairment, poor bone health and metabolic syndrome. For other forms of muscular dystrophy like the limb girdle dystrophies, glucocorticoids are not typically used. Here we review the experimental evidence supporting multiple mechanisms of glucocorticoid action in dystrophic muscle including their role in dampening inflammation and myofiber injury. We also discuss alternative dosing strategies as well as novel steroid agents that are in development and testing, with the goal to reduce adverse consequences of prolonged glucocorticoid exposure while maximizing beneficial outcomes.
Topics: Animals; Anti-Inflammatory Agents; Glucocorticoids; Humans; Immunologic Factors; Muscle, Skeletal; Muscular Dystrophies; Muscular Dystrophy, Duchenne
PubMed: 33104035
DOI: 10.3233/JND-200556 -
Muscle & Nerve May 2018Cardiac disease is a common clinical manifestation present in a variety of neuromuscular disorders, most notably the muscular dystrophies. Heart disease may produce the... (Review)
Review
Cardiac disease is a common clinical manifestation present in a variety of neuromuscular disorders, most notably the muscular dystrophies. Heart disease may produce the presenting or predominant symptoms in these disorders but more often not does not result in clinical features at the time of initial presentation. Cardiac involvement in the muscular dystrophies results from pathologic changes in the myocardium and the cardiac conduction system, leading to cardiomyopathy and/or rhythm disturbances including supraventricular arrhythmias, life-threatening ventricular arrhythmias, and sudden cardiac death. This Review covers the spectrum of cardiac dysfunction in these inherited muscle disorders and proposes practical recommendations for monitoring and management. Muscle Nerve 57: 707-715, 2018.
Topics: Heart Diseases; Humans; Muscular Dystrophies; Myocardium
PubMed: 29130502
DOI: 10.1002/mus.26014 -
Neuromuscular Disorders : NMD Oct 2021Congenital muscular dystrophies (CMDs) are a group of inherited conditions defined by muscle weakness occurring before the acquisition of ambulation, delayed motor... (Review)
Review
Congenital muscular dystrophies (CMDs) are a group of inherited conditions defined by muscle weakness occurring before the acquisition of ambulation, delayed motor milestones, and characterised by muscle dystrophic pathology. A large number of genes - at least 35- are responsible for CMD phenotypes, and it is therefore not surprising that CMDs comprise a wide spectrum of phenotypes, with variable involvement of cardiac/respiratory muscles, central nervous system, and ocular structures. The identification of several new genes over the past few years has further expanded both the clinical and the molecular spectrum underlying CMDs. Comprehensive gene panels allow to arrive at a final diagnosis in around 60% of cases, suggesting that both new genes, and unusual mutations of the currently known genes are likely to account for the remaining cases. The aim of this review is to present the most recent advances in this field. We will outline recent natural history studies that provide additional information on disease progression, discuss recently discovered genes and the current status of the most promising therapeutic options.
Topics: Disease Progression; Humans; Laminin; Muscular Dystrophies; Mutation; Phenotype
PubMed: 34470717
DOI: 10.1016/j.nmd.2021.07.009 -
European Journal of Pharmacology Dec 2021Muscular dystrophy is a well-known genetically heterogeneous group of rare muscle disorders. This progressive disease causes the breakdown of skeletal muscles over time... (Review)
Review
Muscular dystrophy is a well-known genetically heterogeneous group of rare muscle disorders. This progressive disease causes the breakdown of skeletal muscles over time and leads to grave weakness. This breakdown is caused by a diverse pattern of mutations in dystrophin and dystrophin associated protein complex. These mutations lead to the production of altered proteins in response to which, the body stimulates production of various cytokines and immune cells, particularly reactive oxygen species and NFκB. Immune cells display/exhibit a dual role by inducing muscle damage and muscle repair. Various anti-oxidants, anti-inflammatory and glucocorticoid drugs serve as potent therapeutics for muscular dystrophy. Along with the above mentioned therapeutics, induced pluripotent stem cells also serve as a novel approach paving a way for personalized treatment. These pluripotent stem cells allow regeneration of large numbers of regenerative myogenic progenitors that can be administered in muscular dystrophy patients which assist in the recovery of lost muscle fibers. In this review, we have summarized gene-editing, immunological and induced pluripotent stem cell based therapeutics for muscular dystrophy treatment.
Topics: Animals; Dystrophin; Gene Editing; Humans; Induced Pluripotent Stem Cells; Muscular Dystrophies; NF-kappa B; Reactive Oxygen Species
PubMed: 34656607
DOI: 10.1016/j.ejphar.2021.174568