Tag: skeletal muscle

Myalgic encephalomyelitis/chronic fatigue syndrome from current evidence to new diagnostic perspectives through skeletal muscle and metabolic disturbances

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a demanding medical condition for patients and society. It has raised much more public awareness after the COVID-19 pandemic since ME/CFS and long-COVID patients share many clinical symptoms such as debilitating chronic fatigue. However, unlike long COVID, the etiopathology of ME/CFS remains a mystery despite several decades’ research.

This review moves from pathophysiology of ME/CFS through the compelling evidence and most interesting hypotheses. It focuses on the pathophysiology of skeletal muscle by proposing the hypothesis that skeletal muscle tissue offers novel opportunities for diagnosis and treatment of this syndrome and that new evidence can help resolve the long-standing debate on terminology.

Source: Pietrangelo T, Cagnin S, Bondi D, Santangelo C, Marramiero L, Purcaro C, Bonadio RS, Di Filippo ES, Mancinelli R, Fulle S, Verratti V, Cheng X. Myalgic encephalomyelitis/chronic fatigue syndrome from current evidence to new diagnostic perspectives through skeletal muscle and metabolic disturbances. Acta Physiol (Oxf). 2024 Mar 14:e14122. doi: 10.1111/apha.14122. Epub ahead of print. PMID: 38483046. https://pubmed.ncbi.nlm.nih.gov/38483046/

Muscle abnormalities worsen after post-exertional malaise in long COVID

Abstract:

A subgroup of patients infected with SARS-CoV-2 remain symptomatic over three months after infection. A distinctive symptom of patients with long COVID is post-exertional malaise, which is associated with a worsening of fatigue- and pain-related symptoms after acute mental or physical exercise, but its underlying pathophysiology is unclear.

With this longitudinal case-control study (NCT05225688), we provide new insights into the pathophysiology of post-exertional malaise in patients with long COVID. We show that skeletal muscle structure is associated with a lower exercise capacity in patients, and local and systemic metabolic disturbances, severe exercise-induced myopathy and tissue infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID worsen after induction of post-exertional malaise. This study highlights novel pathways that help to understand the pathophysiology of post-exertional malaise in patients suffering from long COVID and other post-infectious diseases.

Source: Appelman, B., Charlton, B.T., Goulding, R.P. et al. Muscle abnormalities worsen after post-exertional malaise in long COVID. Nat Commun 15, 17 (2024). https://doi.org/10.1038/s41467-023-44432-3 https://www.nature.com/articles/s41467-023-44432-3 (Full text)

Microvascular Capillary and Precapillary Cardiovascular Disturbances Strongly Interact to Severely Affect Tissue Perfusion and Mitochondrial Function in ME/CFS Evolving from the Post COVID-19 Syndrome

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a frequent, debilitating and still enigmatic disease. There is a broad overlap in the symptomatology of ME/CFS and the Post-COVID Syndrome (PCS). A fraction of the PCS patients develops the full clinical picture of ME/CFS.
New observations in microvessels and blood from patients suffering from PCS have appeared and include microclots and malformed pathological blood cells. Capillary blood flow is impaired not only by pathological blood components but also by prothrombotic changes in the vascular wall, endothelial dysfunction, and expression of adhesion molecules in the capillaries. These disturbances can finally cause a low capillary flow and even capillary stasis. A low cardiac stroke volume due to hypovolemia and the inability of the capacitance vessels to adequately constrict to deliver the necessary cardiac preload generate an unfavorable low precapillary perfusion pressure.
Furthermore, a predominance of vasoconstrictor over vasodilator influences exists, in which sympathetic hyperactivity and endothelial dysfunction play a strong role, causing constriction of resistance vessels and of precapillary sphincters which leads to a fall in capillary pressure behind the sphincters. The interaction of these two precapillary cardiovascular mechanisms causing a low capillary perfusion pressure is hemodynamically highly unfavorable in the presence of a primary capillary stasis already caused by the pathological blood components and their interaction with the capillary wall, to severely impair organ perfusion.
The detrimental coincidence of the microcirculatory with the precapillary cardiovascular disturbances may constitute the key disturbance of the Post-COVID-19 syndrome and finally lead to ME/CFS in pre-disposed patients because the interaction causes a particular kind of perfusion disturbance – capillary ischemia-reperfusion – which has a high potential of causing mitochondrial dysfunction by inducing sodium- and calcium-overload in skeletal muscles. The latter in turns worsens the vascular situation by the generation of reactive oxygen species to close a vicious cycle from which the patient can hardly escape.
Source: Wirth, K.J.; Löhn, M. Microvascular Capillary and Precapillary Cardiovascular Disturbances Strongly Interact to Severely Affect Tissue Perfusion and Mitochondrial Function in ME/CFS Evolving from the Post COVID-19 Syndrome. Preprints 2023, 2023120791. https://doi.org/10.20944/preprints202312.0791.v1  https://www.preprints.org/manuscript/202312.0791/v1 (Full text available as PDF file)

Post-COVID exercise intolerance is associated with capillary alterations and immune dysregulations in skeletal muscles

Abstract:

The SARS-CoV-2 pandemic not only resulted in millions of acute infections worldwide, but also in many cases of post-infectious syndromes, colloquially referred to as “long COVID”. Due to the heterogeneous nature of symptoms and scarcity of available tissue samples, little is known about the underlying mechanisms.

We present an in-depth analysis of skeletal muscle biopsies obtained from eleven patients suffering from enduring fatigue and post-exertional malaise after an infection with SARS-CoV-2. Compared to two independent historical control cohorts, patients with post-COVID exertion intolerance had fewer capillaries, thicker capillary basement membranes and increased numbers of CD169+ macrophages. SARS-CoV-2 RNA could not be detected in the muscle tissues.

In addition, complement system related proteins were more abundant in the serum of patients with PCS, matching observations on the transcriptomic level in the muscle tissue. We hypothesize that the initial viral infection may have caused immune-mediated structural changes of the microvasculature, potentially explaining the exercise-dependent fatigue and muscle pain.

Source: Aschman, T., Wyler, E., Baum, O. et al. Post-COVID exercise intolerance is associated with capillary alterations and immune dysregulations in skeletal muscles. acta neuropathol commun 11, 193 (2023). https://doi.org/10.1186/s40478-023-01662-2 https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-023-01662-2 (Full text)

Post-acute Sequelae of SARS Co-V2 and Chronic Fatigue/Myalgic Encephalitis Share Similar Pathophysiologic Mechanisms of Exercise Limitation

Abstract:

Abstract available online: https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A6470

Source: S. Jothi, G. Claessen, M. Insel, S. Kubba, E. Howden, S.-R. Carmona, F.P. Rischard. Post-acute Sequelae of SARS Co-V2 and Chronic Fatigue/Myalgic Encephalitis Share Similar Pathophysiologic Mechanisms of Exercise Limitation. https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A6470

Sarcopenia as potential biological substrate of long COVID-19 syndrome: prevalence, clinical features, and risk factors

Abstract:

Background: Severe clinical pictures and sequelae of COVID-19 disease are immune mediated and characterized by a ‘cytokine storm’. Skeletal muscle has emerged as a potent regulator of immune system function. The aim of the present study is to define the prevalence of sarcopenia among COVID-19 survivors and the negative impact of sarcopenia on the post-acute COVID-19 syndrome and its related risk factors.

Methods: A total of 541 subjects recovered from COVID-19 disease were enrolled in the Gemelli Against COVID-19 Post-Acute Care between April 2020 and February 2021. They underwent a multidisciplinary clinical evaluation and muscle strength and physical performance assessment.

Results: Mean age was 53.1 years (SD 15.2, range from 18 to 86 years), and 274 (51%) were women. The prevalence of sarcopenia was 19.5%, and it was higher in patients with a longer hospital stay and lower in patients who were more physically active and had higher levels of serum albumin. Patients with sarcopenia had a higher number of persistent symptoms than non-sarcopenic patients (3.8 ± 2.9 vs. 3.2 ± 2.8, respectively; P = 0.06), in particular fatigue, dyspnoea, and joint pain.

Conclusions: Sarcopenia identified according to the EWGSOP2 criteria is high in patients recovered from COVID-19 acute illness, particularly in those who had experienced the worst clinical picture reporting the persistence of fatigue and dyspnoea. Our data suggest that sarcopenia, through the persistence of inflammation, could be the biological substrate of long COVID-19 syndrome. Physical activity, especially if associated with adequate nutrition, seems to be an important protective factor.

Source: Martone AM, Tosato M, Ciciarello F, Galluzzo V, Zazzara MB, Pais C, Savera G, Calvani R, Marzetti E, Robles MC, Ramirez M, Landi F; Gemelli Against COVID-19 Post-Acute Care Team. Sarcopenia as potential biological substrate of long COVID-19 syndrome: prevalence, clinical features, and risk factors. J Cachexia Sarcopenia Muscle. 2022 Jun 14. doi: 10.1002/jcsm.12931. Epub ahead of print. PMID: 35698920. https://onlinelibrary.wiley.com/doi/10.1002/jcsm.12931 (Full text)

Myopathy as a cause of fatigue in long-term post-COVID-19 symptoms: Evidence of skeletal muscle histopathology

Abstract:

Background: Among post-COVID-19 symptoms, fatigue is reported as one of the most common, even after mild acute infection, and as the cause of fatigue, myopathy diagnosed by electromyography has been proposed in previous reports. This study aimed to explore the histopathological changes in patients with post-COVID-19 fatigue.

Methods: Sixteen patients (mean age:46 years) with post-COVID-19 complaints of fatigue, myalgia or weakness persisting for up to 14 months were included. In all patients, quantitative electromyography and muscle biopsies analysed with light and electron microscopy were taken.

Results: Muscle weakness was present in 50%, myopathic electromyography in 75% while in all patients, there were histological changes. Muscle fiber atrophy was found in 38%, and 56% showed indications of fiber regeneration. Mitochondrial changes, comprising loss of COX activity, subsarcollemmal accumulation and/or abnormal cristae, were present in 62%. Inflammation was found in 62%, seen as T-lymphocytes and/or muscle fiber HLA-ABC expression. In 75%, capillaries were affected involving basal lamina and cells. In two patients, uncommon amounts of basal lamina were found, not only surrounding muscle fibers but also around nerves and capillaries.

Conclusions: The wide variety of histological changes in this study suggest that skeletal muscles may be a major target of SARS-CoV-2 causing muscular post-COVID-19 symptoms. The mitochondrial changes, inflammation and capillary injury in muscle biopsies can cause fatigue in part due to reduced energy supply. Since most patients had mild-moderate acute affection, the new variants that might cause less severe acute disease could still have the ability to cause long-term myopathy.

Source: Hejbøl EK, Harbo T, Agergaard J, Madsen LB, Pedersen TH, Østergaard LJ, Andersen H, Schrøder HD, Tankisi H. Myopathy as a cause of fatigue in long-term post-COVID-19 symptoms: Evidence of skeletal muscle histopathology. Eur J Neurol. 2022 Jun 6. doi: 10.1111/ene.15435. Epub ahead of print. PMID: 35661354.  https://pubmed.ncbi.nlm.nih.gov/35661354/ https://pubmed.ncbi.nlm.nih.gov/35661354/ (Full text available as PDF file)

Skeletal muscle alterations in patients with acute Covid-19 and post-acute sequelae of Covid-19

Abstract:

Background and methods: Skeletal muscle-related symptoms are common in both acute Covid-19 and Post-Acute Sequelae of Covid-19 (PASC). In this narrative review, we discuss cellular and molecular pathways that are affected, and consider these in regard to skeletal muscle involvement in other conditions, such as acute respiratory distress syndrome, critical illness myopathy and post-viral fatigue syndrome.
Results: Patients with severe Covid-19 and PASC suffer from skeletal muscle weakness and exercise intolerance. Histological sections present muscle fiber atrophy, metabolic alterations, and immune cell infiltration. Contributing factors to weakness and fatigue in patients with severe Covid-19 include systemic inflammation, disuse, hypoxemia, and malnutrition. These factors also contribute to post-ICU syndrome and ICU-acquired weakness, and likely explain a substantial part of Covid-19-acquired weakness. The skeletal muscle weakness and exercise intolerance associated with PASC are more obscure and different factors likely contribute. Direct SARS-CoV-2 viral infiltration into skeletal muscle or an aberrant immune system likely contribute. Similarities between skeletal muscle alterations in PASC and chronic fatigue syndrome deserve further study.
Conclusion: Both SARS-CoV-2 specific factors and generic consequences of acute disease likely underlie the observed skeletal muscle alterations in both acute Covid 19 and PASC.
Source: Soares, M., Eggelbusch, M., Naddaf, E., Gerrits, K., van der Schaaf, M., van den Borst, B., Wiersinga, W. J., et al. Skeletal muscle alterations in patients with acute Covid-19 and post-acute sequelae of Covid-19. Journal of Cachexia, Sarcopenia and Muscle. https://doi.org/10.17863/CAM.78509 https://www.repository.cam.ac.uk/handle/1810/331064

Pathophysiology of skeletal muscle disturbances in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Chronic Fatigue Syndrome or Myalgic Encephaloymelitis (ME/CFS) is a frequent debilitating disease with an enigmatic etiology. The finding of autoantibodies against ß2-adrenergic receptors (ß2AdR) prompted us to hypothesize that ß2AdR dysfunction is of critical importance in the pathophysiology of ME/CFS.

Our hypothesis published previously considers ME/CFS as a disease caused by a dysfunctional autonomic nervous system (ANS) system: sympathetic overactivity in the presence of vascular dysregulation by ß2AdR dysfunction causes predominance of vasoconstrictor influences in brain and skeletal muscles, which in the latter is opposed by the metabolically stimulated release of endogenous vasodilators (functional sympatholysis). An enigmatic bioenergetic disturbance in skeletal muscle strongly contributes to this release. Excessive generation of these vasodilators with algesic properties and spillover into the systemic circulation could explain hypovolemia, suppression of renin (paradoxon) and the enigmatic symptoms. In this hypothesis paper the mechanisms underlying the energetic disturbance in muscles will be explained and merged with the first hypothesis.

The key information is that ß2AdR also stimulates the Na+/K+-ATPase in skeletal muscles. Appropriate muscular perfusion as well as function of the Na+/K+-ATPase determine muscle fatigability. We presume that dysfunction of the ß2AdR also leads to an insufficient stimulation of the Na+/K+-ATPase causing sodium overload which reverses the transport direction of the sodium-calcium exchanger (NCX) to import calcium instead of exporting it as is also known from the ischemia-reperfusion paradigm. The ensuing calcium overload affects the mitochondria, cytoplasmatic metabolism and the endothelium which further worsens the energetic situation (vicious circle) to explain postexertional malaise, exercise intolerance and chronification.

Reduced Na+/K+-ATPase activity is not the only cause for cellular sodium loading. In poor energetic situations increased proton production raises intracellular sodium via sodium-proton-exchanger subtype-1 (NHE1), the most important proton-extruder in skeletal muscle. Finally, sodium overload is due to diminished sodium outward transport and enhanced cellular sodium loading. As soon as this disturbance would have occurred in a severe manner the threshold for re-induction would be strongly lowered, mainly due to an upregulated NHE1, so that it could repeat at low levels of exercise, even by activities of everyday life, re-inducing mitochondrial, metabolic and vascular dysfunction to perpetuate the disease.

Source: Wirth KJ, Scheibenbogen C. Pathophysiology of skeletal muscle disturbances in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). J Transl Med. 2021 Apr 21;19(1):162. doi: 10.1186/s12967-021-02833-2. PMID: 33882940.  https://pubmed.ncbi.nlm.nih.gov/33882940/

Substrate utilisation of cultured skeletal muscle cells in patients with CFS

Abstract:

Chronic fatigue syndrome (CFS) patients often suffer from severe muscle pain and an inability to exercise due to muscle fatigue. It has previously been shown that CFS skeletal muscle cells have lower levels of ATP and have AMP-activated protein kinase dysfunction. This study outlines experiments looking at the utilisation of different substrates by skeletal muscle cells from CFS patients (n = 9) and healthy controls (n = 11) using extracellular flux analysis.

Results show that CFS skeletal muscle cells are unable to utilise glucose to the same extent as healthy control cells. CFS skeletal muscle cells were shown to oxidise galactose and fatty acids normally, indicating that the bioenergetic dysfunction lies upstream of the TCA cycle. The dysfunction in glucose oxidation is similar to what has previously been shown in blood cells from CFS patients.

The consistency of cellular bioenergetic dysfunction in different cell types supports the hypothesis that CFS is a systemic disease. The retention of bioenergetic defects in cultured cells indicates that there is a genetic or epigenetic component to the disease. This is the first study to use cells derived from skeletal muscle biopsies in CFS patients and healthy controls to look at cellular bioenergetic function in whole cells.

Source: Tomas C, Elson JL, Newton JL, Walker M. Substrate utilisation of cultured skeletal muscle cells in patients with CFS. Sci Rep. 2020 Oct 26;10(1):18232. doi: 10.1038/s41598-020-75406-w. PMID: 33106563.  https://www.nature.com/articles/s41598-020-75406-w (Full text)