The transforming growth factor-beta (TGF-β) superfamily consists of a variety of cytokines expressed in many different cell types including skeletal muscle. Members of this superfamily that are of particular importance in skeletal muscle are TGF-β1, mitogen-activated protein kinases (MAPKs), and myostatin. These signaling molecules play important roles in skeletal muscle homeostasis and in a variety of inherited and acquired neuromuscular disorders. Expression of these molecules is linked to normal processes in skeletal muscle such as growth, differentiation, regeneration, and stress response. However, chronic elevation of TGF-β1, MAPKs, and myostatin is linked to various features of muscle pathology, including impaired regeneration and atrophy. In this review, we focus on the aberrant signaling of TGF-β in various disorders such as Marfan syndrome, muscular dystrophies, sarcopenia, and critical illness myopathy. We also discuss how the inhibition of several members of the TGF-β signaling pathway has been implicated in ameliorating disease phenotypes, opening up novel therapeutic avenues for a large group of neuromuscular disorders.
Increased activity of the TGF-β superfamily plays an important role in the pathogenesis of both inherited and acquired forms of neuromuscular disorders. These alterations cause an unfavorable environment for muscle regeneration and promote an increase in fibrotic tissue formation (Figure 2). Future studies will need to address the precise timeline of alterations in TGF-β signaling in various disease processes in order to establish the optimal therapeutic intervention. A number of drugs (Table 1; Table 2) are close to or currently in clinical trials. These and future clinical trials will need to establish the safety and efficacy of these drugs and address whether certain clinical conditions may benefit from a multi-targeted approach.
Neuromuscular abnormalities culminating in skeletal-muscle weakness occur very commonly in critically ill patients. Intensive-care-unit (ICU) acquired neuromuscular abnormalities are typically divided into 2 discrete classes: polyneuropathy and myopathy. However, it is likely that these 2 entities commonly coexist, with myopathy being the most common cause of weakness. Major risk factors for ICU-acquired neuromuscular abnormalities include sepsis, corticosteroid administration, and hyperglycemia, with other associated factors including neuromuscular blockade and increasing severity of illness. The pathogenesis of these disorders is not well defined, but probably involves inflammatory injury of nerve and/or muscle that is potentiated by functional denervation and corticosteroids. ICU-acquired neuromuscular abnormalities are associated with multiple adverse outcomes, including higher mortality, prolonged duration of mechanical ventilation, and increased length of stay. The only intervention proven to reduce the incidence of ICU-acquired neuromuscular abnormalities is intensive insulin therapy. Additional research is necessary to better delineate the causes and pathogenesis of these disorders and to identify potential preventive and therapeutic strategies. In addition, consensus guidelines for its classification and diagnosis are needed.
Intensive care unit-acquired weakness (ICU-AW), a common neuromuscular complication associated with patients in the ICU, is a type of skeletal muscle dysfunction that commonly occurs following sepsis, mobility restriction, hyperglycemia, and the use of glucocorticoids or neuromuscular blocking agents. ICU-AW can lead to delayed withdrawal of mechanical ventilation and extended hospitalization. Patients often have poor prognosis, limited mobility, and severely affected quality of life. Currently, its pathogenesis is uncertain, with unavailability of specific drugs or targeted therapies. ICU-AW has gained attention in recent years. This manuscript reviews the current research status of the epidemiology, pathogenesis, diagnosis, and treatment methods for ICU-AW and speculates the novel perspectives for future research.
Neuromuscular diseases can be acquired or genetic. Mutations of more than 500 genes have shown to be causes of neuromuscular diseases. Other causes include nerve or muscle degeneration, autoimmunity, toxins, medications, malnutrition, metabolic derangements, hormone imbalances, infection, nerve compression/entrapment, comprised blood supply, and trauma.
Myasthenia gravis (MG) is the most common primary disorder of neuromuscular transmission. The usual cause is an acquired immunological abnormality, but some cases result from genetic abnormalities at the neuromuscular junction. Much has been learned about the pathophysiology and immunopathology of myasthenia gravis during the past 20 years. What was once a relatively obscure condition of interest primarily to neurologists is now the best characterized and understood autoimmune disease. A wide range of potentially effective treatments are available, many of which have implications for the treatment of other autoimmune disorders.
The normal neuromuscular junction releases acetylcholine (ACh) from the motor nerve terminal in discrete packages (quanta). The ACh quanta diffuse across the synaptic cleft and bind to receptors on the folded muscle end-plate membrane. Stimulation of the motor nerve releases many ACh quanta that depolarize the muscle end-plate region and then the muscle membrane causing muscle contraction. In acquired myasthenia gravis, the post-synaptic muscle membrane is distorted and simplified, having lost its normal folded shape. The concentration of ACh receptors on the muscle end-plate membrane is reduced, and antibodies are attached to the membrane. ACh is released normally, but its effect on the post-synaptic membrane is reduced. The post-junctional membrane is less sensitive to applied ACh, and the probability that any nerve impulse will cause a muscle action potential is reduced.
The Journal of Neuromuscular Diseases aims to facilitate progress in understanding the molecular genetics/correlates, pathogenesis, pharmacology, diagnosis and treatment of acquired and genetic neuromuscular diseases (including muscular dystrophy, myasthenia gravis, spinal muscular atrophy, neuropathies, myopathies, myotonias and myositis).
Arthrofibrosis (AF), or rigid contracture of articular joints, is a common morbidity of many neuromuscular disorders (NMDs). AF manifests with appendicular weakness (hypotonia), spasticity, or both. Regardless of etiology (congenital, genetic, or acquired), injuries to the brain, spinal cord, peripheral nerves, or muscles often result in loss of active and dynamic joint motion. The decreased excursion of joints through their full range of motion (ROM), due to loss of neuromuscular motor activity and/or agonist-antagonist muscle imbalance, results in stagnant positioning of the joint over prolonged periods. Inmobilization with limited joint ROM provokes a pericapsular accumulation of fibrotic collagenous tissue and further limits mobility . In addition, primary muscle pathology (i.e., fibrofatty tissue replacement) contribute to structural changes that reduce myotendinous extensibility .
Hypertrophic neuropathies include a variety of disorders with variable involvement of motor and sensory nerves. Charcot-Marie-Tooth disease (also known as hereditary motor and sensory neuropathy) is the most common inherited neuromuscular disease and Chronic Inflammatory Demyelinating Polyneuropathy (or Polyradiculoneuropathy) is likely the most recognized acquired immune-mediated peripheral neuropathy.1,2
COVID-19 is a disease caused by SARS-CoV-2 with pulmonary, cardiovascular, neurologic, and other multi-organ manifestations. Despite the fact that millions worldwide have been infected, we still do not understand many of the pathophysiologic mechanisms underlying COVID-19 disease. Our lab has acquired NIH funding to support basic and translational research into the pathogenesis of SARS-CoV-2. This includes mechanisms of viral spread, pulmonary disease, and neuromuscular disease. Additionally, we have created multiple novel mouse models of SARS-CoV-2 infection to model COVID-19 to study how it spreads throughout the body and damage various organs. This work has important implications in understanding the course of viral infection and may reveal novel insights into Long COVID (sustained symptoms after viral clearance). 59ce067264