muscle function – American ME and CFS Society

Muscular metabolic plasticity in 3D in vitro models against systemic stress factors in ME/CFS and long COVID-19

Abstract:

Myalgic encephalomyelities/ chronic fatigue syndrome and long COVID-19 are clinically challenging, multi-symptomatic conditions with multiple overlapping symptoms. Unfortunately, contemporary research is directly being done on patients which risks exacerbating their symptoms. Using our 3-D in vitro skeletal muscle tissues we have mapped the progression of functional, physiological, and metabolic adaptations of the tissues in response to patient sera over time.

During short exposure we treated the tissues for 48 hours with patient sera. The contractile profiles of these tissues were severely compromised. Transcriptomic analyses of these short exposure samples showed an absence of significant differentially expressed genes between ME/CFS and LC-19. The analyses revealed an upregulation of glycolytic enzymes especially of PDK4, suggesting a switch away from Oxidative Phosphorylation as well as a decline in DRP1, involved in mitochondrial fission.

Subsequent structural analyses confirmed hypertrophy in myotubes and hyperfused mitochondrial networks. Mitochondrial oxygen consumption capacity, evaluated through the MitoStress test, was also elevated, as was the non-mitochondrial respiration confirming the shift to glycolysis.

Interestingly, at short exposures of 48 hours, the muscle tissues appeared to be adapting to the stress factors by upregulating glycolysis and increasing the muscular metabolic volume. Prolonging the exposure to 96 and 144 hours induced high fatiguability, and fragility in tissues. The mitochondria, at longer exposures, appeared to be fragmented and assumed a toroidal conformation indicating a change in mitochondrial membrane potential.

We hypothesize that the disease progresses through an intermediary stress-induced hypermetabolic state, ultimately leading to severe deterioration of muscle function. This is the first account of research that proposes acquired metabolic plasticity in 3D skeletal muscles exposed to ME/CFS and Long COVID-19 sera.

Source: S. Mughal, F. Andújar-Sánchez, M. Sabater-Arcis, J. Fernández-Costa, J. Ramón-Azcón. 571P Muscular metabolic plasticity in 3D in vitro models against systemic stress factors in ME/CFS and long COVID-19. Neuromuscular Disorders, Volume 43, Supplement 1, October 2024, 104441.162. https://www.sciencedirect.com/science/article/abs/pii/S0960896624003353

Maximal Oxidative Capacity During Exercise is Associated with Muscle Power Output in Patients with Long coronavirus disease 2019 (COVID-19) Syndrome. A Moderation Analysis

Abstract:

Background & Aims: Long COVID syndrome (LCS) involves persistent symptoms experienced by many patients after recovering from coronavirus disease 2019 (COVID-19). We aimed to assess skeletal muscle energy metabolism, which is closely related to peak fat oxidation rates during exercise, in patients with LCS compared with healthy controls. We also examined whether muscle power output mediates the relationship between COVID-19 and skeletal muscle energy metabolism.

Methods: In this cross-sectional study, we enrolled 71 patients with LCS and 63 healthy controls. We assessed clinical characteristics such as body composition, physical activity, and muscle strength. We used cardiopulmonary exercise testing to evaluate substrate oxidation rates during graded exercise. We performed statistical analyses to compare group characteristics and peak fat oxidation differences based on power output.

Results: The two-way analysis of covariance (ANCOVA) results, adjusted for covariates, showed that the patients with LCS had lower absolute maximal fatty acid oxidation (MFO), relative MFO/fat-free mass (FFM), absolute carbohydrates oxidation (CHox), relative CHox/FFM, and oxygen uptake (VO₂) at maximum fat oxidation (mL∙min⁻¹) than the healthy controls (P < 0.05). Moderation analysis indicated that muscle power output significantly influenced the relationship between LCS and reduced peak fat oxidation (interaction β = −0.105 [95% confidence interval −0.174; −0.036]; P = 0.026). Therefore, when muscle power output was below 388 W, the effect of the LCS on MFO was significant (62% in our study sample P = 0.010). These findings suggest compromised mitochondrial bioenergetics and muscle function, represented by lower peak fat oxidation rates, in the patients with LCS compared with the healthy controls.

Conclusion: The patients with LCS had lower peak fat oxidation during exercise compared with the healthy controls, potentially indicating impairment in skeletal muscle function. The relationship between peak fat oxidation and LCS appears to be mediated predominantly by muscle power output. Additional research should continue investigating LCS pathogenesis and the functional role of mitochondria.

Source: Robinson Ramírez-Vélez, Sergio Oscoz-Ochandorena, Yesenia García-Alonso, Nora García-Alonso, Gaizka Legarra-Gorgoñon, Julio Oteiza, Ander Ernaga Lorea, Mikel Izquierdo, María Correa-Rodríguez. Maximal Oxidative Capacity During Exercise is Associated with Muscle Power Output in Patients with Long coronavirus disease 2019 (COVID-19) Syndrome. A Moderation Analysis. Clinical Nutrition ESPEN, 2023, ISSN 2405-4577, https://doi.org/10.1016/j.clnesp.2023.10.009. https://www.sciencedirect.com/science/article/pii/S2405457723021666 (Full text)

Predictors of Post-COVID-19 Functional Status Scale in hospitalized patients recovering from SARS-CoV-2 infection

Abstract:

Objective: The study aimed to investigate whether peripheral and inspiratory muscle strength and architecture, functional capacity, functional mobility, fatigue and health-related quality of life (HRQoL) are predictors of the PCFS scale score in patients with post-COVID-19 syndrome who were hospitalized.

Design: A cross-sectional study included 69 patients (53.3 ± 13.2 years, 36 men) with post-COVID-19 syndrome. The following outcomes were assessed: peripheral (dynamometry) and inspiratory (manovacuometry) muscle strength, muscle architecture (ultrasound), functional capacity (six-minute walk test), functional mobility (Timed Up and Go), fatigue (Functional Assessment of Chronic Illness Therapy), HRQoL (36-item Short Form Health Survey) and functional status (PCFS scale).

Results: Functional mobility (β = 0.573; P < 0.001), vastus intermedius echogenicity (β = -0.491; P = 0.001), length of stay (β = 0.349; P = 0.007) and female sex (β = 0.415; P = 0.003) influenced the PCFS scale.

Conclusion: Functional mobility, muscle quality of the vastus intermedius, length of stay and female sex influence the PCFS scale score in this population. It is noteworthy that functional mobility is an independent predictor of PCFS scale.

Source: Dos Santos TD, Alves Souza J, Cardoso DM, Berni VB, Pasqualoto AS, de Albuquerque IM. Predictors of Post-COVID-19 Functional Status Scale in hospitalized patients recovering from SARS-CoV-2 infection. Am J Phys Med Rehabil. 2023 Aug 18. doi: 10.1097/PHM.0000000000002325. Epub ahead of print. PMID: 37594212. https://pubmed.ncbi.nlm.nih.gov/37594212/

The Role of Cytokines in Muscle Fatigue in Patients with Chronic Fatigue Syndrome (CFS)

Abstract:

CFS is characterized by profound levels of persistent/recurrent fatigue. It is proposed that chronic, low level inflammation may play a role in this fatigue. We recruited 100 untreated patients with CFS (average age 33±12) and 100 age and sex matched healthy controls (HCs). Serum levels of TNF-α were assessed using ELISA. Subjective fatigue was determined by questionnaire and muscle function tests were undertaken in subgroups in which maximal voluntary contraction (MVC), electrically stimulated muscle force generation and rate of fatigue were assessed in the quadriceps muscle.

Subjective fatigue was higher in patients with CFS compared with HCs. Preliminary analyses showed that serum TNF-α was undetectable in 97% of HCs, whereas 15% of patients with CFS had detectable (4.4+/-0.18pg/ml) serum TNF-α. MVC was significantly reduced in subjects with CFS compared with HCs. No difference was seen in stimulated muscle fatigue between groups.

This preliminary data suggests that a sub-group of patients with CFS may have low level inflammation and analyses are underway to further characterise other inflammatory markers in serum and muscle of these patients and to determine whether such changes could affect indices of muscle function or central fatigue.

Funded by MRC, BBSRC and the ME Association.

Source: Earl, K., Sakellariou, G., Owens, D., Sinclair, M., Fenech, M., Close, G., Lawton, C., Dye, L., Beadsworth, M. and McArdle, A. (2015), The Role of Cytokines in Muscle Fatigue in Patients with Chronic Fatigue Syndrome (CFS). The FASEB Journal, 29: 1055.34. https://doi.org/10.1096/fasebj.29.1_supplement.1055.34 https://faseb.onlinelibrary.wiley.com/doi/10.1096/fasebj.29.1_supplement.1055.34 (Full text)

Can recovery of peripheral muscle function predict cognitive task performance in chronic fatigue syndrome with and without fibromyalgia?

Abstract:

BACKGROUND: Both good physical and cognitive functioning have a positive influence on the execution of activities of daily living. Patients with chronic fatigue syndrome (CFS) as well as patients with fibromyalgia have marked cognitive deficits. Furthermore, a good physical and functional health status may have a positive impact on a variety of cognitive skills-a link that has been observed in young and old individuals who are healthy, although evidence is limited in patients with CFS.

OBJECTIVE: The purpose of this study was to examine whether recovery of upper limb muscle function could be a significant predictor of cognitive performance in patients with CFS and in patients with CFS and comorbid fibromyalgia. Furthermore, this study determined whether cognitive performance is different between these patient groups.

DESIGN: A case-control design was used.

METHODS: Seventy-eight participants were included in the study: 18 patients with CFS only (CFS group), 30 patients with CFS and comorbid fibromyalgia (CFS+FM group), and 30 individuals who were healthy and inactive (control group) were studied. Participants first completed 3 performance-based cognitive tests designed to assess selective and sustained attention, cognitive inhibition, and working memory capacity. Seven days later, they performed a fatiguing upper limb exercise test, with subsequent recovery measures.

RESULTS: Recovery of upper limb muscle function was found to be a significant predictor of cognitive performance in patients with CFS. Participants in the CFS+FM group but not those in the CFS group showed significantly decreased cognitive performance compared with the control group.

LIMITATIONS: The cross-sectional nature of this study does not allow for inferences of causation.

CONCLUSIONS: The results suggest that better physical health status could predict better mental health in patients with CFS. Furthermore, they underline disease heterogeneity, suggesting that reducing this factor in future research is important to better understand and uncover mechanisms regarding the nature of diverse impairments in these patients.

Source: Ickmans K, Meeus M, De Kooning M, Lambrecht L, Pattyn N, Nijs J. Can recovery of peripheral muscle function predict cognitive task performance in chronic fatigue syndrome with and without fibromyalgia? Phys Ther. 2014 Apr;94(4):511-22. doi: 10.2522/ptj.20130367. Epub 2013 Dec 20. https://www.ncbi.nlm.nih.gov/pubmed/24363336

Recovery of upper limb muscle function in chronic fatigue syndrome with and without fibromyalgia

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) patients frequently complain of muscle fatigue and abnormally slow recovery, especially of the upper limb muscles during and after activities of daily living. Furthermore, disease heterogeneity has not yet been studied in relation to recovery of muscle function in CFS. Here, we examine recovery of upper limb muscle function from a fatiguing exercise in CFS patients with (CFS+FM) and without (CFS-only) comorbid fibromyalgia and compare their results with a matched inactive control group.

DESIGN: In this case-control study, 18 CFS-only patients, 30 CFS+FM patients and 30 healthy inactive controls performed a fatiguing upper limb exercise test with subsequent recovery measures.

RESULTS: There was no significant difference among the three groups for maximal handgrip strength of the non-dominant hand. A significant worse recovery of upper limb muscle function was found in the CFS+FM, but not in de CFS-only group compared with the controls (P < 0·05).

CONCLUSIONS: This study reveals, for the first time, delayed recovery of upper limb muscle function in CFS+FM, but not in CFS-only patients. The results underline that CFS is a heterogeneous disorder suggesting that reducing the heterogeneity of the disorder in future research is important to make progress towards a better understanding and uncovering of mechanisms regarding the nature of divers impairments in these patients.

Source: Ickmans K, Meeus M, De Kooning M, Lambrecht L, Nijs J. Recovery of upper limb muscle function in chronic fatigue syndrome with and without fibromyalgia. Eur J Clin Invest. 2014 Feb;44(2):153-9. doi: 10.1111/eci.12201. Epub 2013 Dec 9. https://www.ncbi.nlm.nih.gov/pubmed/24313704

Red cell shape changes following trigger finger fatigue in subjects with chronic tiredness and healthy controls

Abstract:

AIMS: To investigate the possibility of a correlation between the percentage of nondiscocytic erythrocytes and muscle fatiguability in subjects with the symptom of chronic tiredness.

METHODS: Sixty nine volunteers suffering from persisting or intermittent tiredness and 72 healthy controls provided 3-drop samples of venous blood for red cell shape analysis before and after inducing fatigue in the trigger finger muscles by repeatedly pulling the trigger of an antique revolver. Elapsed time and the number of pulls were recorded. A work index was calculated from the number of trigger pulls divided by the time in seconds then multiplied by the number of trigger pulls.

RESULTS: Subjects with tiredness had fewer discoid cells (males 62.5% vs 69.2%, p = 0.029; females 65.8% vs 71.8%, p = 0.002) than controls. They also had fewer trigger pulls (males 62.3 vs 84.0, p = 0.003; females 29.5 vs 36.8, p = 0.042) and lower “work indices” (males 75.6 vs 104.7, p = 0.001; females 26.1 vs 39.6, p = 0.001) than controls at the first trigger pulling. After 5 minutes rest the number of trigger pulls for males was fewer than the controls (56.0 vs 64.2) but the difference was not significant, but the female values (24.3 vs 33.2) were significantly different (p = 0.008). Work indices for both sexes were significantly different from controls (males p = 0.020, females p = 0.001).

CONCLUSIONS: The association of increased nondiscocytes and impaired muscle function could indicate a cause and effect relationship. This would be in agreement with the physiological concept of fatigue as a consequence of inadequate oxygen delivery.

Source: Simpson LO, Murdoch JC, Herbison GP. Red cell shape changes following trigger finger fatigue in subjects with chronic tiredness and healthy controls. N Z Med J. 1993 Mar 24;106(952):104-7. http://www.ncbi.nlm.nih.gov/pubmed/8474717

Chronic fatigue syndrome: studies on skeletal muscle

Abstract:

Chronic fatigue syndrome represents a poorly defined disease with protean clinical manifestations, the majority of them expressed as a muscle fatigue or as inability to maintain the expected muscle strength.

In the present work we studied muscle function and muscle histopathology in 20 patients fulfilling the proposed criteria for chronic fatigue syndrome. Special interest is directed towards the immunoreactive expression of class I MHC molecules comparing some inflammatory and virus-related myopathies with muscles from chronic fatigue syndrome.

Only minor morphological changes were detected in 9 out of 20 patients of the series. The nonspecific morphological changes in muscle tissue and the lack of class I MHC expression does not support the viral etiology of muscle fatigue in chronic fatigue syndrome. In contrast with the reported clinical improvement with high doses of essential fatty acids, our patients’ clinical condition did not improve after three months of L-carnitine therapy.

Source: Grau JM, Casademont J, Pedrol E, Fernández-Solà J, Cardellach F, Barros N, Urbano-Márquez A. Chronic fatigue syndrome: studies on skeletal muscle. Clin Neuropathol. 1992 Nov-Dec;11(6):329-32. http://www.ncbi.nlm.nih.gov/pubmed/1473316