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1.
Cells ; 10(10)2021 09 23.
Article in English | MEDLINE | ID: covidwho-1438524

ABSTRACT

The ability of the ribonucleic acid (RNA) to self-replicate, combined with a unique cocktail of chemical properties, suggested the existence of an RNA world at the origin of life. Nowadays, this hypothesis is supported by innovative high-throughput and biochemical approaches, which definitively revealed the essential contribution of RNA-mediated mechanisms to the regulation of fundamental processes of life. With the recent development of SARS-CoV-2 mRNA-based vaccines, the potential of RNA as a therapeutic tool has received public attention. Due to its intrinsic single-stranded nature and the ease with which it is synthesized in vitro, RNA indeed represents the most suitable tool for the development of drugs encompassing every type of human pathology. The maximum effectiveness and biochemical versatility is achieved in the guise of non-coding RNAs (ncRNAs), which are emerging as multifaceted regulators of tissue specification and homeostasis. Here, we report examples of coding and ncRNAs involved in muscle regeneration and discuss their potential as therapeutic tools. Small ncRNAs, such as miRNA and siRNA, have been successfully applied in the treatment of several diseases. The use of longer molecules, such as lncRNA and circRNA, is less advanced. However, based on the peculiar properties discussed below, they represent an innovative pool of RNA biomarkers and possible targets of clinical value.


Subject(s)
MicroRNAs/metabolism , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , RNA, Messenger/metabolism , RNA, Untranslated/genetics , Regeneration , Animals , Biomarkers/metabolism , COVID-19 , Homeostasis , Humans , Mice , Muscle, Skeletal/virology , Myocardium/metabolism , Origin of Life , RNA, Circular , RNA, Long Noncoding/genetics , RNA, Small Interfering/metabolism , RNA, Small Untranslated/genetics , RNA, Viral/metabolism , SARS-CoV-2/genetics
3.
Front Immunol ; 12: 676828, 2021.
Article in English | MEDLINE | ID: covidwho-1320577

ABSTRACT

In coronavirus disease 2019 (COVID-19), ulcerative lesions have been episodically reported in various segments of the gastrointestinal (GI) tract, including the oral cavity, oropharynx, esophagus, stomach and bowel. In this report, we describe an autopsy case of a COVID-19 patient who showed two undiagnosed ulcers at the level of the anterior and posterior walls of the hypopharynx. Molecular testing of viruses involved in pharyngeal ulcers demonstrated the presence of severe acute respiratory syndrome - coronavirus type 2 (SARS-CoV-2) RNA, together with herpes simplex virus 1 DNA. Histopathologic analysis demonstrated full-thickness lympho-monocytic infiltration (mainly composed of CD68-positive cells), with hemorrhagic foci and necrosis of both the mucosal layer and deep skeletal muscle fibers. Fibrin and platelet microthrombi were also found. Cytological signs of HSV-1 induced damage were not found. Cells expressing SARS-CoV-2 spike subunit 1 were immunohistochemically identified in the inflammatory infiltrations. Immunohistochemistry for HSV1 showed general negativity for inflammatory infiltration, although in the presence of some positive cells. Thus, histopathological, immunohistochemical and molecular findings supported a direct role by SARS-CoV-2 in producing local ulcerative damage, although a possible contributory role by HSV-1 reactivation cannot be excluded. From a clinical perspective, this autopsy report of two undiagnosed lesions put the question if ulcers along the GI tract could be more common (but frequently neglected) in COVID-19 patients.


Subject(s)
COVID-19/complications , Hypopharynx/pathology , SARS-CoV-2/isolation & purification , Ulcer/pathology , Aged , Antigens, CD/metabolism , Antigens, Differentiation, Myelomonocytic/metabolism , Autopsy , Blood Platelets/metabolism , Blood Platelets/pathology , COVID-19/mortality , COVID-19/pathology , COVID-19/physiopathology , Gastrointestinal Tract/pathology , Herpesvirus 1, Human/genetics , Herpesvirus 1, Human/isolation & purification , Humans , Hypopharynx/virology , Immunohistochemistry , Inflammation/immunology , Inflammation/metabolism , Inflammation/virology , Lymphocytes/metabolism , Monocytes/metabolism , Mucous Membrane/pathology , Muscle, Skeletal/pathology , Necrosis/pathology , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/metabolism , Thrombosis/pathology , Ulcer/virology
4.
JAMA Neurol ; 78(8): 948-960, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1265359

ABSTRACT

Importance: Myalgia, increased levels of creatine kinase, and persistent muscle weakness have been reported in patients with COVID-19. Objective: To study skeletal muscle and myocardial inflammation in patients with COVID-19 who had died. Design, Setting, and Participants: This case-control autopsy series was conducted in a university hospital as a multidisciplinary postmortem investigation. Patients with COVID-19 or other critical illnesses who had died between March 2020 and February 2021 and on whom an autopsy was performed were included. Individuals for whom informed consent to autopsy was available and the postmortem interval was less than 6 days were randomly selected. Individuals who were infected with SARS-CoV-2 per polymerase chain reaction test results and had clinical features suggestive of COVID-19 were compared with individuals with negative SARS-CoV-2 polymerase chain reaction test results and an absence of clinical features suggestive of COVID-19. Main Outcomes and Measures: Inflammation of skeletal muscle tissue was assessed by quantification of immune cell infiltrates, expression of major histocompatibility complex (MHC) class I and class II antigens on the sarcolemma, and a blinded evaluation on a visual analog scale ranging from absence of pathology to the most pronounced pathology. Inflammation of cardiac muscles was assessed by quantification of immune cell infiltrates. Results: Forty-three patients with COVID-19 (median [interquartile range] age, 72 [16] years; 31 men [72%]) and 11 patients with diseases other than COVID-19 (median [interquartile range] age, 71 [5] years; 7 men [64%]) were included. Skeletal muscle samples from the patients who died with COVID-19 showed a higher overall pathology score (mean [SD], 3.4 [1.8] vs 1.5 [1.0]; 95% CI, 0-3; P < .001) and a higher inflammation score (mean [SD], 3.5 [2.1] vs 1.0 [0.6]; 95% CI, 0-4; P < .001). Relevant expression of MHC class I antigens on the sarcolemma was present in 23 of 42 specimens from patients with COVID-19 (55%) and upregulation of MHC class II antigens in 7 of 42 specimens from patients with COVID-19 (17%), but neither were found in any of the controls. Increased numbers of natural killer cells (median [interquartile range], 8 [8] vs 3 [4] cells per 10 high-power fields; 95% CI, 1-10 cells per 10 high-power fields; P < .001) were found. Skeletal muscles showed more inflammatory features than cardiac muscles, and inflammation was most pronounced in patients with COVID-19 with chronic courses. In some muscle specimens, SARS-CoV-2 RNA was detected by reverse transcription-polymerase chain reaction, but no evidence for a direct viral infection of myofibers was found by immunohistochemistry and electron microscopy. Conclusions and Relevance: In this case-control study of patients who had died with and without COVID-19, most individuals with severe COVID-19 showed signs of myositis ranging from mild to severe. Inflammation of skeletal muscles was associated with the duration of illness and was more pronounced than cardiac inflammation. Detection of viral load was low or negative in most skeletal and cardiac muscles and probably attributable to circulating viral RNA rather than genuine infection of myocytes. This suggests that SARS-CoV-2 may be associated with a postinfectious, immune-mediated myopathy.


Subject(s)
COVID-19/pathology , Muscle, Skeletal/pathology , Myocarditis/pathology , Myocardium/pathology , Myositis/pathology , Aged , Aged, 80 and over , Autopsy , CD8-Positive T-Lymphocytes/pathology , COVID-19/metabolism , COVID-19 Nucleic Acid Testing , COVID-19 Serological Testing , Case-Control Studies , Female , Histocompatibility Antigens Class I/metabolism , Histocompatibility Antigens Class II/metabolism , Humans , Killer Cells, Natural/pathology , Leukocytes/pathology , Macrophages/pathology , Male , Middle Aged , Muscle, Skeletal/metabolism , Myocarditis/metabolism , Myocardium/metabolism , Myositis/metabolism , RNA, Viral/metabolism , SARS-CoV-2 , Sarcolemma/metabolism , Time Factors
5.
Neurology ; 97(8): e849-e858, 2021 08 24.
Article in English | MEDLINE | ID: covidwho-1261289

ABSTRACT

OBJECTIVE: To explore the spectrum of skeletal muscle and nerve pathology of patients who died after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and to assess for direct viral invasion of these tissues. METHODS: Psoas muscle and femoral nerve sampled from 35 consecutive autopsies of patients who died after SARS-CoV-2 infection and 10 SARS-CoV-2-negative controls were examined under light microscopy. Clinical and laboratory data were obtained by chart review. RESULTS: In SARS-CoV-2-positive patients, mean age at death was 67.8 years (range 43-96 years), and the duration of symptom onset to death ranged from 1 to 49 days. Four patients had neuromuscular symptoms. Peak creatine kinase was elevated in 74% (mean 959 U/L, range 29-8,413 U/L). Muscle showed type 2 atrophy in 32 patients, necrotizing myopathy in 9, and myositis in 7. Neuritis was seen in 9. Major histocompatibility complex-1 (MHC-1) expression was observed in all cases of necrotizing myopathy and myositis and in 8 additional patients. Abnormal expression of myxovirus resistance protein A (MxA) was present on capillaries in muscle in 9 patients and in nerve in 7 patients. SARS-CoV-2 immunohistochemistry was negative in muscle and nerve in all patients. In the 10 controls, muscle showed type 2 atrophy in all patients, necrotic muscle fibers in 1, MHC-1 expression in nonnecrotic/nonregenerating fibers in 3, MxA expression on capillaries in 2, and inflammatory cells in none, and nerves showed no inflammatory cells or MxA expression. CONCLUSIONS: Muscle and nerve tissue demonstrated inflammatory/immune-mediated damage likely related to release of cytokines. There was no evidence of direct SARS-CoV-2 invasion of these tissues. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that muscle and nerve biopsies document a variety of pathologic changes in patients dying of coronavirus disease 2019 (COVID-19).


Subject(s)
COVID-19/pathology , Muscle, Skeletal/pathology , Peripheral Nerves/pathology , Adult , Aged , Aged, 80 and over , Autopsy , COVID-19/immunology , COVID-19/virology , Female , Humans , Male , Middle Aged , Muscle, Skeletal/immunology , Muscle, Skeletal/virology , Peripheral Nerves/immunology , Peripheral Nerves/virology
6.
Skelet Muscle ; 11(1): 10, 2021 04 21.
Article in English | MEDLINE | ID: covidwho-1197351

ABSTRACT

BACKGROUND: SARS-CoV2 virus could be potentially myopathic. Serum creatinine phosphokinase (CPK) is frequently found elevated in severe SARS-CoV2 infection, which indicates skeletal muscle damage precipitating limb weakness or even ventilatory failure. CASE PRESENTATION: We addressed such a patient in his forties presented with features of severe SARS-CoV2 pneumonia and high serum CPK. He developed severe sepsis and acute respiratory distress syndrome (ARDS) and received intravenous high dose corticosteroid and tocilizumab to counter SARS-CoV2 associated cytokine surge. After 10 days of mechanical ventilation (MV), weaning was unsuccessful albeit apparently clear lung fields, having additionally severe and symmetric limb muscle weakness. Ancillary investigations in addition with serum CPK, including electromyogram, muscle biopsy, and muscle magnetic resonance imaging (MRI) suggested acute myopathy possibly due to skeletal myositis. CONCLUSION: We wish to stress that myopathogenic medication in SARS-CoV2 pneumonia should be used with caution. Additionally, serum CPK could be a potential marker to predict respiratory failure in SARS-CoV2 pneumonia as skeletal myopathy affecting chest muscles may contribute ventilatory failure on top of oxygenation failure due to SARS-CoV2 pneumonia.


Subject(s)
COVID-19/physiopathology , Creatine Kinase/blood , Muscle, Skeletal/physiopathology , Muscular Diseases/physiopathology , Quadriplegia/physiopathology , Respiratory Distress Syndrome/physiopathology , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Adult , Alanine/analogs & derivatives , Alanine/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Anticoagulants/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/complications , COVID-19/therapy , Critical Illness , Dexamethasone/therapeutic use , Electromyography , Glucocorticoids/therapeutic use , Heparin, Low-Molecular-Weight/therapeutic use , Humans , Intensive Care Units , Magnetic Resonance Imaging , Male , Methicillin-Resistant Staphylococcus aureus , Muscle, Skeletal/diagnostic imaging , Muscle, Skeletal/pathology , Muscular Diseases/blood , Muscular Diseases/diagnosis , Muscular Diseases/etiology , Neural Conduction , Pulmonary Embolism/diagnosis , Pulmonary Embolism/drug therapy , Pulmonary Embolism/etiology , Pulmonary Embolism/physiopathology , Quadriplegia/etiology , Respiration, Artificial , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/therapy , SARS-CoV-2 , Severity of Illness Index , Staphylococcal Infections/complications , Staphylococcal Infections/diagnosis , Staphylococcal Infections/drug therapy , Ventilator Weaning
7.
J Immunoassay Immunochem ; 41(6): 1000-1009, 2020 Nov 01.
Article in English | MEDLINE | ID: covidwho-1104704

ABSTRACT

Autopsies represent medical procedures through which the causes of patients' deaths are determined or, through tissue sampling and microscopic examination of slides in usual stains or special tests, one can offer the basis for understanding the physiopathological mechanisms that contribute to the patients' death Histological findings of tissue samples from patients who have died of COVID-19 have been mainly orientated to lung, heart, liver, kidney damage with a small percent of them following other organs, but none has, to our knowledge, studied skeletal muscle.


Subject(s)
COVID-19/pathology , Muscle, Skeletal/pathology , Muscle, Skeletal/virology , Necrosis , Autopsy , Creatine Kinase/blood , Endothelium, Vascular/pathology , Fatal Outcome , Humans , Inflammation , Ischemia/pathology , Kidney Tubules/pathology , Male , Middle Aged , Muscle, Skeletal/immunology , Tissue Distribution
11.
Clin Neurophysiol ; 131(12): 2809-2816, 2020 12.
Article in English | MEDLINE | ID: covidwho-898641

ABSTRACT

OBJECTIVE: Coronavirus disease 2019 (COVID-19) has a high incidence of intensive care admittance due to the severe acute respiratory syndrome (SARS). Intensive care unit (ICU)-acquired weakness (ICUAW) is a common complication of ICU patients consisting of symmetric and generalised weakness. The aim of this study was to determine the presence of myopathy, neuropathy or both in ICU patients affected by COVID-19 and whether ICUAW associated with COVID-19 differs from other aetiologies. METHODS: Twelve SARS CoV-2 positive patients referred with the suspicion of critical illness myopathy (CIM) or polyneuropathy (CIP) were included between March and May 2020. Nerve conduction and concentric needle electromyography were performed in all patients while admitted to the hospital. Muscle biopsies were obtained in three patients. RESULTS: Four patients presented signs of a sensory-motor axonal polyneuropathy and seven patients showed signs of myopathy. One muscle biopsy showed scattered necrotic and regenerative fibres without inflammatory signs. The other two biopsies showed non-specific myopathic findings. CONCLUSIONS: We have not found any distinctive features in the studies of the ICU patients affected by SARS-CoV-2 infection. SIGNIFICANCE: Further studies are needed to determine whether COVID-19-related CIM/CIP has different features from other aetiologies. Neurophysiological studies are essential in the diagnosis of these patients.


Subject(s)
COVID-19/complications , Intensive Care Units , Muscular Diseases/etiology , Polyneuropathies/etiology , SARS-CoV-2 , Aged , Biopsy , Critical Illness , Electromyography/methods , Female , Humans , Male , Middle Aged , Muscle Weakness/diagnosis , Muscle Weakness/etiology , Muscle Weakness/pathology , Muscle, Skeletal/pathology , Muscular Diseases/diagnosis , Muscular Diseases/pathology , Muscular Diseases/physiopathology , Neural Conduction , Polyneuropathies/diagnosis , Polyneuropathies/physiopathology
12.
Neurol Sci ; 42(3): 1119-1121, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-866217

ABSTRACT

We found four patients with some characteristic phenotype in our ICU, characterized by focal hypotrophies of the shoulder girdle and the bilateral peroneal district and underlying critical illness neuro-myopathy. In our opinion, these hypotrophies are secondary to the prone position. Is our intention to start early treatment protocol with electrostimulation to evaluate the effectiveness in the prevention of critical illness and focal hypotrophies in ICU SARS-CoV-2 patients, to increase chances of returning to a preinfection functional status.


Subject(s)
COVID-19/complications , Muscular Diseases/virology , Polyneuropathies/virology , Aged , Female , Humans , Intensive Care Units , Male , Middle Aged , Muscle, Skeletal/pathology , Prone Position , SARS-CoV-2
13.
Indian J Med Res ; 152(1 & 2): 41-47, 2020.
Article in English | MEDLINE | ID: covidwho-732738

ABSTRACT

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been predominantly a respiratory manifestation. Currently, with evolving literature, neurological signs are being increasingly recognized. Studies have reported that SARS-CoV-2 affects all aspects of the nervous system including the central nervous system (CNS), peripheral nervous system (PNS) and the muscular system as well. Not all patients have reverse transcription-polymerase chain reaction positive for the virus in the cerebrospinal fluid, and diagnosing the association of the virus with the myriad of neurological manifestations can be a challenge. It is important that clinicians have a high-index of suspicion for COVID-19 in patients presenting with new-onset neurological symptoms. This will lead to early diagnosis and specific management. Further studies are desired to unravel the varied neurological manifestations, treatment, outcome and long-term sequel in COVID-19 patients.


Subject(s)
Central Nervous System/pathology , Coronavirus Infections/epidemiology , Nervous System Diseases/epidemiology , Peripheral Nervous System/pathology , Pneumonia, Viral/epidemiology , Betacoronavirus/pathogenicity , COVID-19 , Central Nervous System/virology , Coronavirus Infections/complications , Coronavirus Infections/pathology , Coronavirus Infections/virology , Humans , Muscle, Skeletal/pathology , Muscle, Skeletal/virology , Nervous System Diseases/complications , Nervous System Diseases/pathology , Nervous System Diseases/virology , Pandemics , Peripheral Nervous System/virology , Pneumonia, Viral/complications , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , SARS-CoV-2
14.
Mol Med ; 26(1): 69, 2020 07 08.
Article in English | MEDLINE | ID: covidwho-635101

ABSTRACT

BACKGROUND: We previously showed that the autophagy inhibitor chloroquine (CQ) increases inflammatory cleaved caspase-1 activity in myocytes, and that caspase-1/11 is protective in sterile liver injury. However, the role of caspase-1/11 in the recovery of muscle from ischemia caused by peripheral arterial disease is unknown. We hypothesized that caspase-1/11 mediates recovery in muscle via effects on autophagy and this is modulated by CQ. METHODS: C57Bl/6 J (WT) and caspase-1/11 double-knockout (KO) mice underwent femoral artery ligation (a model of hind-limb ischemia) with or without CQ (50 mg/kg IP every 2nd day). CQ effects on autophagosome formation, microtubule associated protein 1A/1B-light chain 3 (LC3), and caspase-1 expression was measured using electron microscopy and immunofluorescence. Laser Doppler perfusion imaging documented perfusion every 7 days. After 21 days, in situ physiologic testing in tibialis anterior muscle assessed peak force contraction, and myocyte size and fibrosis was also measured. Muscle satellite cell (MuSC) oxygen consumption rate (OCR) and extracellular acidification rate was measured. Caspase-1 and glycolytic enzyme expression was detected by Western blot. RESULTS: CQ increased autophagosomes, LC3 consolidation, total caspase-1 expression and cleaved caspase-1 in muscle. Perfusion, fibrosis, myofiber regeneration, muscle contraction, MuSC fusion, OCR, ECAR and glycolytic enzyme expression was variably affected by CQ depending on presence of caspase-1/11. CQ decreased perfusion recovery, fibrosis and myofiber size in WT but not caspase-1/11KO mice. CQ diminished peak force in whole muscle, and myocyte fusion in MuSC and these effects were exacerbated in caspase-1/11KO mice. CQ reductions in maximal respiration and ATP production were reduced in caspase-1/11KO mice. Caspase-1/11KO MuSC had significant increases in protein kinase isoforms and aldolase with decreased ECAR. CONCLUSION: Caspase-1/11 signaling affects the response to ischemia in muscle and effects are variably modulated by CQ. This may be critically important for disease treated with CQ and its derivatives, including novel viral diseases (e.g. COVID-19) that are expected to affect patients with comorbidities like cardiovascular disease.


Subject(s)
Caspase 1/metabolism , Caspases, Initiator/metabolism , Chloroquine/pharmacology , Coronavirus Infections/pathology , Ischemia/pathology , Muscle, Skeletal/pathology , Pneumonia, Viral/pathology , Animals , Autophagosomes/metabolism , Autophagy/drug effects , Betacoronavirus , COVID-19 , Coronavirus Infections/drug therapy , Glycolysis/physiology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Microtubule-Associated Proteins/metabolism , Muscle Cells/metabolism , Muscle Development , Muscle, Skeletal/metabolism , Neovascularization, Physiologic , Oxidative Phosphorylation , Pandemics , Peripheral Arterial Disease/pathology , Pneumonia, Viral/drug therapy , Regeneration , SARS-CoV-2 , Signal Transduction
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