Persistent Fatigue, Weakness, and Aberrant Muscle Mitochondria in Survivors of Critical COVID-19, 2024, Kirby P Mayer et al

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KEY POINTS
Question: Determine the short- and long-term physical impairments and skeletal muscle cellular changes in survivors of critical COVID.

Findings: Survivors of critical COVID have high prevalence of weakness, fatigue, and reduced functional exercise capacity with muscle tissue exhibiting a greater abundance of M2-like macrophages and satellite cells and lower activity of mitochondrial complex II and complex IV.

Meanings: Perturbed muscle recovery associates with fatigue and poor physical function months after ICU admission for COVID-19. Critical care and post-hospital clinicians should be aware of the potential long-term muscle deficits in COVID survivors, but more work is needed to understand the mechanisms underlying these histochemical findings and their relationship to long COVID.

Abstract
OBJECTIVES:
Persistent skeletal muscle dysfunction in survivors of critical illness due to acute respiratory failure is common, but biological data elucidating underlying mechanisms are limited. The objective of this study was to elucidate the prevalence of skeletal muscle weakness and fatigue in survivors of critical illness due to COVID-19 and determine if cellular changes associate with persistent skeletal muscle dysfunction.

DESIGN:
A prospective observational study in two phases: 1) survivors of critical COVID-19 participating in physical outcome measures while attending an ICU Recovery Clinic at short-term follow-up and 2) a nested cohort of patients performed comprehensive muscle and physical function assessments with a muscle biopsy; data were compared with non-COVID controls.

MEASUREMENTS AND MAIN RESULTS:
One hundred twenty patients with a median of 56 years old (interquartile range [IQR], 42–65 yr old), 43% female, and 33% individuals of underrepresented race attended follow-up 44 ± 17 days after discharge. Patients had a median Acute Physiology and Chronic Health Evaluation-II score of 24.0 (IQR, 16–29) and 98 patients (82%) required mechanical ventilation with a median duration of 14 days (IQR, 9–21 d). At short-term follow-up significant physical dysfunction was observed with 93% of patients reporting generalized fatigue and performing mean 218 ± 151 meters on 6-minute walk test (45% ± 30% of predicted). Eleven patients from this group agreed to participate in long-term assessment and muscle biopsy occurring a mean 267 ± 98 days after discharge. Muscle tissue from COVID exhibited a greater abundance of M2-like macrophages and satellite cells and lower activity of mitochondrial complex II and complex IV compared with controls.

CONCLUSIONS:
Our findings suggest that aberrant repair and altered mitochondrial activity in skeletal muscle associates with long-term impairments in patients surviving an ICU admission for COVID-19.
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Summarising the different muscle types from Skeletal muscle fiber type: using insights from muscle developmental biology to dissect targets for susceptibility and resistance to muscle disease (2016, Wiley Interdisciplinary Reviews: Developmental Biology) —

• Skeletal muscle fibers are broadly classified as "slow-twitch" (type 1) and "fast-twitch" (type 2).

• Based on differential myosin heavy chain (MYH) gene expression, there is further classification of fast-twitch fibers into three major subtypes (types 2A, 2X, and 2B, although humans do not appear to have MYH4-expressing type 2B fibers)

• Hybrid MYH expression in different fibers of a muscle group can allow for even more subtypes (1/2A, 2A/2X, 2X/2B), resulting in an almost continuous range of ATP usage and muscle contraction speeds, from the fastest (type 2B) to the slowest (type 1).

• Skeletal muscle fibers also vary in energy production. Type 1 and 2A fibers primarily use oxidative metabolism, and type 2X and 2B fibers primarily rely upon glycolytic metabolism. However, even here there is variation, and energy usage is not a strict predictor of fiber type.

Findings in the current paper relate to Muscle abnormalities worsen after post-exertional malaise in long COVID (2024, Nature Communications)

Patients in COVID group had a lower percentage of type 1 and higher percentage of type 2a/x muscle fibers compared with controls. There were no differences in average or type 1 or 2a specific muscle fiber cross-sectional area but COVID had larger type 2a/x fibers compared with controls.

To assess muscle mitochondrial activity, we used SDH histochemistry in conjunction with immunohistochemistry for MyHC expression. Muscle from COVID exhibited a lower percentage of SDH dark fibers and higher percentage of SDH light fibers compared with controls, indicating lower muscle mitochondrial enzyme activity. Also, mitochondrial enzyme activity was lower in both type 1 and 2a fibers. No differences were observed within type 2a/x muscle fibers. COVID had lower cytochrome c oxidase (CCO) activity than controls, but no differences were observed in citrate synthase (CS) activity; the ratio between CCO and CS was significantly lower in muscle from COVID compared with control, indicating lower mitochondrial enzyme activity.

Significant correlations were observed between total number of SDH light stained fibers with 6MWT

 

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Discussion —

Our findings suggest that metabolic alterations including reduced muscle mitochondrial activity with higher percentage of type 2a/x muscle fibers combined with higher abundances of M2-like macrophages associate with long-term physical impairments after ICU admission for COVID-19. The cellular finding of increased M2-like macrophages which are important for tissue remodeling suggest a perturbated muscle repair occurring several months after hospital discharge. Our data in patients recovering from critical COVID-19 align with recent studies in individuals with long COVID without ICU admission. Of clinical importance, muscle mitochondrial deficits in our patients associated with fatigue and physical function.

A lower prevalence of type 1 and higher type 2a/x myofibers may also explain the high rates of fatigue reported in our study. Previous work demonstrate that muscle fibers shift from type 1 toward type 2 in metabolic disease and during bedrest explaining the biogenetic inefficiency (type 2 fibers produce lower amounts of adenosine triphosphate [ATP]). Fiber type shifts may also occur in response to targeted exercise training and thus critical COVID survivors may benefit from long-term exercise strategies.

Muscle biopsies in survivors of critical illness due to mixed etiologies, demonstrated reduced SC [satellite cell] content, increased collagen deposition, and muscle fiber atrophy. Our findings suggest that sustained atrophy does not solely explain functional deficits after critical COVID as mitochondrial alterations were strongly related to fatigue and performance in our patients even despite small sample sizes.

It should be noted that the study did not compare individuals with an ICU admission for non-COVID to those with COVID; therefore, we cannot conclude that the observed deficits are related to COVID-19 alone and not due to any generalized critical illness requiring ICU admission.