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Review
. 2022 Nov;32(6):e2355.
doi: 10.1002/rmv.2355. Epub 2022 Apr 13.

Muscle dysfunction in the long coronavirus disease 2019 syndrome: Pathogenesis and clinical approach

Camilla Costa Silva  1 , Clea Nazaré Carneiro Bichara  1 , Francisca Regina Oliveira Carneiro  1 , Vera Regina da Cunha Menezes Palacios  1 , Ana Virgínia Soares Van den Berg  1 , Juarez Antônio Simões Quaresma  1 , Luiz Fábio Magno Falcão  1
Affiliations
Review

Muscle dysfunction in the long coronavirus disease 2019 syndrome: Pathogenesis and clinical approach

Camilla Costa Silva et al. Rev Med Virol. 2022 Nov.

Abstract

In long coronavirus disease 2019 (long COVID-19), involvement of the musculoskeletal system is characterised by the persistence or appearance of symptoms such as fatigue, muscle weakness, myalgia, and decline in physical and functional performance, even at 4 weeks after the onset of acute symptoms of COVID-19. Muscle injury biomarkers are altered during the acute phase of the disease. The cellular damage and hyperinflammatory state induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may contribute to the persistence of symptoms, hypoxaemia, mitochondrial damage, and dysregulation of the renin-angiotensin system. In addition, the occurrence of cerebrovascular diseases, involvement of the peripheral nervous system, and harmful effects of hospitalisation, such as the use of drugs, immobility, and weakness acquired in the intensive care unit, all aggravate muscle damage. Here, we review the multifactorial mechanisms of muscle tissue injury, aggravating conditions, and associated sequelae in long COVID-19.

Keywords: long COVID-19; muscle; muscle dysfunction; muscle sequelae.

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Conflict of interest statement

The authors declare that they have no conflict of interest declared.

Figures

FIGURE 1
FIGURE 1
Pathogenesis of muscle dysfunction caused by SARS‐CoV‐2. 1: SARS‐CoV‐2 infects the muscle cell and uses cell machinery for replication, resulting in cell death and tissue damage. 2: SARS‐CoV‐2 infects lung cells, causing a local inflammatory response, diffuse alveolar damage, and hypoxaemia, interfering with myogenesis and myogenic differentiation and muscle metabolism and energy production. 3: SARS‐CoV‐2 infection of endothelial cells results in inflammation, hypercoagulation, and vasoconstriction, leading to neurotoxicity and cell death. 4: The binding of SARS‐CoV‐2 to angiotensin‐converting enzyme 2 (ACE2) negatively regulates the activity of the enzyme, favouring the high expression of angiotensin II (Ang2) and its receptor, angiotensin type 1 receptor (ATR1), leading to muscle atrophy and fibrosis. 5: The exacerbation of inflammation in the lungs increases inflammatory mediators, which are transported by the blood to other organs and systems. In the muscle, inflammatory cytokines increased muscle proteolysis and decreased protein synthesis. In the peripheral nervous system, antibodies attack nerves, causing damage to the axon or myelin. 6: Hospitalisation due to COVID‐19 can cause muscle damage due to the use of drugs and sedatives, as well as mechanical ventilation and immobility. 1, 2, 3, 4, 5, and 6 lead to muscle dysfunction, characterised by decreased synthesis and increased protein degradation, increased oxidative stress, myonuclear apoptosis, and mitochondrial dysfunction. This figure was created with Biorender.com
FIGURE 2
FIGURE 2
Cerebrovascular complications and neural damage caused by SARS‐CoV‐2 infection and its inflammatory response. Cerebrovascular complications caused by SARS‐CoV‐2: the virus binds to angiotensin‐converting enzyme 2 (ACE2) of endothelial cells, depleting these receptors and increasing the levels of angiotensin II (Ang II) in the blood. Elevated Ang II levels result in inflammation, leading to clot formation and potential ischaemic stroke, vasoconstriction, and fluid retention, with increased blood pressure and potential haemorrhagic stroke. In both events, the consequences include microvascular disarray, hypoxia, metabolic and electrical changes, and vasogenic oedema, leading to neurotoxicity and cell death. The sequelae of cerebrovascular events involve severe muscle wasting, muscle weakness, and hemiparesis. Peripheral nervous system damage: the intense inflammatory response resulting from a viral infection can induce nerve destruction via an autoimmune response, characterised by damage to the axons and myelin sheath. As a result, dysfunction in the neuromuscular junction, myopathies, and polyneuropathies can occur, such as Guillain‐Barré syndrome, generating flaccid paralysis with severe loss of muscle mass and sensory damage. This figure was created with Biorender.com
FIGURE 3
FIGURE 3
Hyperinflammatory state induces mitochondrial damage and myopathy in long COVID‐19. 1: Inflammatory mediators carried by the bloodstream reach the muscle tissue. 2: Interferon‐gamma (IFN‐γ), interleukin 1 beta (IL‐1β), interleukin 6 (IL‐6), interleukin 17 (IL‐17), and tumour necrosis factor‐alpha (TNF‐α) are at increased levels. 3: Cytokines induce increased proteolysis of muscle fibre and muscle fibroblasts, decreased protein synthesis, differentiation, and proliferation of satellite cells, and decreased myogenesis and dysregulation of nuclear factor‐kappa beta (NF‐Kβ). Muscle injury is characterised by increased infiltrating natural killer (NK) cells, major histocompatibility complex (MHC) class I and II antigens, and necrotic fibres. In addition, the increase in muscle cytokine levels inhibits the activity of the mammalian target of rapamycin complex 1 (mTORC1), resulting in mitochondrial damage, impairing the production of adenosine triphosphate (ATP). 4: The occurrence of symptoms such as muscle weakness, fatigue, myalgia, and the decline in physical performance are consequences of muscle atrophy resulting from tissue damage. This figure was created with Biorender.com
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References

    1. Taribagil P, Creer D, Tahir H. Long COVID syndrome. BMJ Case Rep. 2021;14:e241485. 10.1136/bcr-2020-241485 - DOI - PMC - PubMed
    1. Dennis A, Wamil M, Alberts J, et al. Multiorgan impairment in low‐risk individuals with post‐COVID‐19 syndrome: a prospective, Community‐based study. BMJ Open. 2021;11:e048391. 10.1136/bmjopen-2020-048391 - DOI - PMC - PubMed
    1. Sigfrid L, Drake T, Pauley E. Long Covid in adults discharged from UK hospitals after Covid‐19: a prospective, multicentre cohort study using the ISARIC WHO Clinical Characterisation Protocol. Lancet Reg Health Eur. 2021;8:100186. 10.1016/j.lanepe.2021.100186 - DOI - PMC - PubMed
    1. Yong SJ. Long COVID or post‐COVID‐19 syndrome: putative pathophysiology, risk factors, and treatments. Inf Disp. 2021;53:737‐754. 10.1080/23744235.2021.1924397 - DOI - PMC - PubMed
    1. Nalbandian A, Sehgal K, Gupta A, et al. Post‐acute COVID‐19 syndrome. Nat Med. 2021;27(4):601‐615. 10.1038/s41591-021-01283-z - DOI - PMC - PubMed