In a recent study published in Reviews in Medical Virology, researchers reviewed the mechanisms of muscle tissue injury, aggravating conditions, and associated sequelae in long coronavirus disease 2019 (COVID‐19).
Study: Muscle dysfunction in the long coronavirus disease 2019 syndrome: Pathogenesis and clinical approach. Image Credit: Anatomy Image/Shutterstock
Background
In long COVID‐19, musculoskeletal system involvement secondary to the hyperinflammatory state is characterized by the persistence of clinical symptoms such as myalgia, fatigue, muscle weakness, and decline in functional and physical performance, even after four weeks of symptom onset. In addition, mitochondrial damage, hypoxemia, and dysregulation of the renin-angiotensin system (RAS) occur.
COVID-19-associated hospitalization, immobility and drugs, cerebrovascular disorders, and involvement of the central and peripheral nervous systems aggravate muscle damage, which is characterized by reduced protein synthesis and decreased muscle mass. An in-depth understanding of the pathophysiology of muscle dysfunction could aid in the development of novel muscle management strategies to curb COVID-19-associated sequelae.
About the review
In the present study, researchers elucidated the mechanisms of the impact of long COVID-19 on the musculoskeletal system.
COVID-19 directly impacts the skeletal muscles or worsens already existing muscle injury, establishing effects on muscles characterized as a) primary, infecting the muscle cells, leading to cellular death; b) secondary, due to derangements in systems such as the respiratory system, central and peripheral nervous systems, c) tertiary, due to COVID-19 cytokine storm (peripheral neuropathy and myopathy); and d) quaternary, due prolonged immobilization (progressive reduction in muscle mass) and hospitalization (mechanical ventilation, drugs, myopathy, and neuropathy).
Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) enters the cells of hosts by binding to angiotensin-converting enzyme 2 (ACE2), and this binding is potentiated by transmembrane serine protease 2 (TMPRSS2). The musculoskeletal tissues express TMPRSS2 and ACE2 and are thus, susceptible to COVID-19. It is highly probable that once bound to ACE2, the virus enters the muscle cells by endocytosis.
In endosomes, viral proteins fuse to cellular membranes on TMPRSS2 activation, resulting in the release of ribonucleic acid (RNA) into the cytoplasm. The virus uses the cellular machinery of the muscle cells for replication, which causes downregulation of cellular muscle functions and thereby causes muscle injury and cell death.
COVID-19 results in severe hypoxemia and requirements of oxygen supplementation and mechanical ventilation. Diffuse alveolar injury with subsequent aggregation of inflammatory substances, deposition of fibrin and collagen, compromised gaseous exchange, and reduced permeability of alveolar capillaries takes place.
The muscle hypoxia leads to impaired oxidative phosphorylation, decreased protein synthesis, reduced mitochondrial activity, and impaired adenosine triphosphate (ATP) generation with increased protein degradation and the resultant reduction in muscle mass. Hypoxia-inducible factor-1 alpha (HIF‐1α)-mediated increase in the pro-inflammatory cytokine levels takes place. Anaerobic glycolysis occurs wherein pyruvate is transformed into lactate by the lactate dehydrogenase (LDH) enzyme. Further, activating Notch pathways, inhibiting phosphoinositide 3‐ kinase pathways, and damage to muscle regulatory factors like Myf5, MyoD, MyoD, etc., cause decreased myogenesis. The reduced peripheral oxygen levels lead to exercise intolerance in long COVID-19.
Nervous system injury
SARS-CoV-2 invades the CNS via the hematogenous route, which involves viral binding to THE endothelial cells of the blood‐brain barrier (BBB), an infection of immune-regulatory cells, olfactory neurons, and the liquor route, wherein infected lymphocytes get attached to endothelial cells of the cerebrospinal fluid (CSF) and reach the glial cells and neurons.
Studies have reported an association between COVID‐19 and the cerebrovascular derangements, with hemorrhagic and ischemic stroke, endothelial cell inflammation, and coagulopathy. These effects are associated increase in angiotensin II (Ang II) expression, which causes clot formation, fluid retention, vasoconstriction, and hypertension.
COVID-19 associated PNS damage involves neuromuscular junction dysfunctions, myopathies, and polyneuropathies. The hypoxia increases vascular permeability, leading to vasogenic edema. COVID-19, associated with Guillain‐Barré syndrome (GBS), is an example of the PNS involvement of COVID-19, in which flaccid paralysis of lower limb muscles develops rapidly post symptom onset.
Dysregulated RAS, hospitalization, and muscle hyper-inflammation
The viral entry decreases ACE2 expression, increasing classical RAS activation leading to muscle fibrosis and atrophy and increased production of reactive oxygen species (ROS). The viral immune escape leads to the production of chemokines and cytokines such as interleukins (IL-26,1β,10), tumor necrosis factor‐alpha (TNF‐α), and interferon‐gamma (IFN‐γ), leading to the immune cell recruitment and cytokine storm, that results in muscle damage.
Elevated cytokine expression is associated with accelerated loss of muscle tissue, decreased muscle contractility, increased muscle fibrosis, muscle fiber proteolysis, deranged muscle homeostasis, and decreased muscle endurance. In addition, inhibition of the mammalian target of rapamycin complex 1 (mTORC1) activity leads to dysregulated mitochondrial function and reduced deoxyribonucleic acid (DNA) production.
Prolonged immobilization and prolonged use of glucocorticoids have been reported to result in muscular atrophy, decreased muscle volume, decreased action potentials, decreased density of type II muscle fibers, axonal damage, and decreased insulin‐like growth factor-1 (IGF‐1) levels.
Muscle sequelae in long COVID‐19
Long COVID-19 patients have substantially increased creatine kinase (CK), cholesterol C‐reactive protein (CRP), lactate dehydrogenase (LDH), ferritin, and cortisol, which affect ATP production and cause increased muscle fatigue and thereby decreased ability to perform routine functions. COVID-19 associated sarcopenia causes physical and functional muscular deterioration in muscle volume and strength with decreased satellite cells and activation of anabolic mechanisms. Further, type 2 diabetes mellitus and obesity exacerbate long COVID-19 complications. Muscle fatigue in long COVID-19 is also associated with cognitive deficits, dyspnea, and reduced lung capacity.
Overall, the review highlights the inflammation, RAS- and hypoxia-associated decrease in muscle mass, strength, size, and volume in long COVID-19, potentiated by prolonged immobilization, drug use, and comorbidities. The review underscores the importance of physical exercise, nutritional monitoring, and other muscle management strategies for long COVID-19 patients.
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