Muscle Abnormalities in Nonhospitalised Patients With Post–COVID-19 Condition, 2025, Tryfonos et al.

[SNT Gatchaman]

Muscle Abnormalities in Nonhospitalised Patients With Post–COVID-19 Condition

Spoiler: Authors

Andrea Tryfonos; Gustav Jörnåker; Håkan Rundqvist; Kaveh Pourhamidi; Michael Melin; Helena Wallin; Filip J Larsen; Spyridon Pantelios; Anders P Mutvei; Veronika Tillander; Uwe J F Tietge; Sergio Perez Diaz; Douglas Crafoord; Alen Lovric; Rodrigo Fernandez-Gonzalo; Eric Rullman; Per Stål; Thomas Gustafsson; Helene Rundqvist; Tommy R Lundberg

BACKGROUND
Post-COVID condition (PCC) affects ~10% of SARS-CoV-2–infected individuals and manifests as persistent symptoms such as fatigue, exercise intolerance and muscle weakness. This study aimed to assess the skeletal muscle of these patients and compare them with healthy controls.

METHODS
Biopsies were obtained from the vastus lateralis muscle of 28 nonhospitalised PCC patients without concomitant diseases (75% women, mean age 46.4 ± 10.4 years) and 28 age-and sex-matched healthy controls (79% women, mean age 46.6 ± 8.7 years). The analysis included morphological and pathological alterations, fibre type composition, fibre cross-sectional area, capillarisation, number of myonuclei, presence of developmental myosin, CD68+ cells, macroautophagy markers, mitochondrial respiration, lipidomics and RNA sequencing.

RESULTS
PCC patients, compared to controls, had a higher percentage of angulated fibres (median [IQR] 0.43 [0.00–3.20] vs. 0.00 [0.00–0.00]; p < 0.001), small, rounded fibres (0.21 [0.00–1.20] vs. 0.00 [0.00–0.00]; p < 0.001) and fibres expressing fetal myosin (0.26 [0.00–1.15] vs. 0.00 [0.00–0.17]; p = 0.015). Semiquantitative analysis showed nuclear clumps (18/27, 66.6%), hypertrophic fibres (9/27, 33.3%) and fibrosis (22/27, 81.4%) in PCC patients. Fibre cross-sectional area was significantly lower in PCC patients (4031 ± 1365 vs. 4982 ± 1463 μm2; p = 0.018), largely driven by differences in type 2 fibre size (3533 ± 1249 vs. 4275 ± 1646 μm2; p = 0.068) than type 1 fibre size (4553 ± 1422 vs. 4932 ± 1380 μm2; p = 0.325). There was a significantly lower number of myonuclei per fibre in PCC (3.4 ± 1.1 vs. 4.1 ± 1.0; p = 0.012), but no difference in the presence of CD68+ per fibre (0.28 ± 0.15 vs. 0.22 ± 1.0; p = 0.115). No group differences were observed in macroautophagy markers LC3B (0.0032 ± 0.0007 vs. 0.0030 ± 0.0006; p = 0.232) or p62 (0.0072 ± 0.0023 vs. 0.0079 ± 0.0016; p = 0.814). Capillary-to-fibre ratio in PCC patients was lower for both type 1 (2.2 ± 0.7 vs. 2.6 ± 0.9; p = 0.044) and type 2 fibres (1.8 ± 0.6, vs. 2.2 ± 0.8; p = 0.022). Mitochondrial respiration was 11–28% lower in PCC patients, although not statistically significant. Lipidomics showed a lower number of phospholipids, and RNA sequencing revealed downregulation of eight metabolic pathways, primarily related to oxidative phosphorylation in PCC patients compared to controls (FDR < 0.05).

CONCLUSIONS
Nonhospitalised patients with PCC show signs of morphological and pathological muscle changes suggestive of degeneration and regeneration. The smaller overall fibre size, lower number of phospholipids, reduced mitochondrial oxidative capacity and lower capillarisation in these patients may be a consequence of reduced physical activity levels. The presence of clusters of atrophied angular and round-shaped fibres, signs of inflammation and fibrosis and increased expression of fetal myosin may reflect myopathic and neurogenic post-viral effects.

TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT05445830.

Web | PDF | Journal of Cachexia, Sarcopenia and Muscle | Open Access

 

[SNT Gatchaman]

They evaluate previously healthy and non-hospitalised long Covid patients, matching controls by age, sex, BMI, daily physical and sedentary activity. They reference and replicate some of the findings from —

Muscle abnormalities worsen after post-exertional malaise in long COVID (2024)

Post-COVID exercise intolerance is associated with capillary alterations and immune dysregulations in skeletal muscles (2023)

Structural and functional impairments of skeletal muscle in patients with post-acute sequelae of SARS-CoV-2 infection (2023)

muscle samples from PCC patients differed from the controls by having a significantly higher proportion of smallsized fibres with an angular (p < 0.001) or rounded form (p < 0.001).

A low amount of necrotic muscle fibres invaded by phagocytes was found in 17/27 (62.9%) […] One PCC case revealed a local area in the muscle characterized by severe fibrosis, fat infiltration and an accumulation of inflammatory cells

Semiquantitative analysis revealed a generally lower mitochondrial NADH-TR staining activity

A significantly higher proportion of fibres expressing fetal [myosin heavy chain] was found in PCC patients compared to controls (p = 0.017)

There was a tendency of lower [cross-sectional area], particularly in type 2 fibres (~17%, p = 0.068), but not in type 1 fibres (p = 0.325)

Fibre type specific analyses showed no difference in fibre type distribution

there was a lower number of CD68+ [macrophages] per muscle area in PCC compared to controls (p = 0.004

Capillary-to-fibre ratio was lower in both type 1 (~16%, p = 0.044) and type 2 fibres (~20%, p = 0.024) […] there was a tendency of a lower number of capillaries irrigating fibres (type 1, p = 0.077; type 2, p = 0.080), as well as capillary-to-fibre perimeter exchange index (type 1, p = 0.052, type 2, p = 0.073)

Mitochondrial respiration was assessed in a subgroup of the cohort (10 patients with PCC and 11 age- and sex-matched controls. […] Although mitochondrial quality […] was numerically lower (~11%–28%) in the PCC group compared to controls, there were no statistical differences between the groups

phospholipid species were significantly lower in PCC patients.

11 genes were differently expressed in PCC patients compared with controls (false discovery rate [FDR] < 0.05), out of which five had a significant fold change (logFC ≥ 0.5). In particular, three genes mainly related to mitochondrial function (NIPSNAP1, logFC = 0.55, FDR = 0.024), metabolite transport (SLC16A12, logFC = 0.51, FDR = 0.009) and endothelial function (PLVAP, logFC = 0.75, FDR = 0.024) were lower expressed in PCC patients compared to controls, whereas two genes related to basic cellular processes including DNA packaging (NAP1L4, logFC = −3.43, FDR = 3.19 × 10−9 ), and tissue repair (RNF122, logFC = −0.503, FDR = 0.024) were higher expressed in PCC patients compared to controls.

Gene-set enrichment analysis identified 8 differentially regulated pathways between patients and controls (FDR < 0.05), all of which had a lower expression in PCC patients than in controls. All the differentially expressed pathways were involved in metabolism, and in particular, oxidative phosphorylation

 

[SNT Gatchaman]

Prior studies —

Non-Hospitalized Patients With Post-COVID Condition and Myopathic Electromyography Findings Show no Difference in Symptom Severity and Clinical Manifestations Compared to Those Without Myopathic Findings (2024)

Functional Limitations and Exercise Intolerance in Patients With Post-COVID Condition: A Randomized Crossover Clinical Trial (2024)

In the discussion and conclusion —

While these changes may perhaps be explained by the lower physical activity levels in the patient cohort, we cannot exclude the possibility of a postviral effect on skeletal muscle, which could then lead to reduced muscle function and exercise capacity.

Taken together, these observations suggest that the PCC-related muscle phenotype consists of a combination of selective fibre atrophy, lower capacity for aerobic metabolism, oxidative stress and reduced vascular support, which likely contributes to the characteristic symptoms of fatigue and reduced exercise capacity and muscle strength.

Our results show that PCC is associated with peripheral impairment and suggest possible skeletal muscle involvement in nonhospitalised, previously healthy patients with persistent PEM symptoms and reduced exercise capacity and muscle strength.

A rehabilitation programme that focuses on strength training may be recommended as it is likely to counteract type 2 fibre atrophy, improve muscle strength, and increase functional capacity without excessive energy demands.

Measures should be taken to cautiously improve physical activity in this cohort to counteract further muscle atrophy and functional decline.

(Remember these were previously healthy people, non-hospitalised, being compared to healthy controls matched to physical activity.)

 

[Turtle]

Nothing wrong with the muscles?
Can't find anything wrong in the brain?
Untill it is researched in a rigorous way.
Two papers in one day you posted @SNT Gatchaman, really helpful.
Highlights as always highly appreciated.

 

[Evergreen]

A rehabilitation programme that focuses on strength training may be recommended as it is likely to counteract type 2 fibre atrophy, improve muscle strength, and increase functional capacity without excessive energy demands.

This could be code for "We have found that these people cannot do aerobic exercise programmes."