Persistent Fatigue, Weakness, and Aberrant Muscle Mitochondria in Survivors of Critical COVID-19

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.

Setting: ICU Recovery Clinic and clinical laboratory.

Patients/subjects: Survivors of critical COVID-19 and non-COVID controls.

Interventions: None.

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.

Figure 1.

Greater CD206+ macrophages and satellite cell (SC) abundance in vastus lateralis muscle biopsies from patients recovering from critical COVID-19. Quantification of macrophage populations in muscle from COVID survivors (n = 9, blue) compared with controls (n = 22, white) including total CD11b+ macrophages, CD11b+CD206+ (M2-like) macrophages, and CD11b+CD206– (M1-like) macrophages (A) with representative images of macrophages in muscle from a COVID survivor (B; white arrows indicating CD11b+ CD206+). Quantification of paired box 7 (Pax7)+/4′,6-diamidino-2-phenylindole+ SCs in muscle from COVID survivors (n = 9, blue) compared with controls (n = 22, white) including total SCs, SCs associated with type 1 muscle fibers, and SCs associated with type 2 muscle fibers (C) with representative images of SCs (D; white and blue arrows indicating SC with type 1 and SC with type 2, respectively). Pax7 data from a subset within the control (n = 15) has been previously published (38). Data are expressed as mean ± sd; p values determined by Mann-Whitney U test; *significance p ≤ 0.05. Images acquired at ×200, scale bar = 100 µm.

Figure 2.

Altered fiber type frequency and fiber size in vastus lateralis muscle from critical COVID. Quantification of fiber type and fiber size within biopsies from COVID patients (n = 9) compared with controls (n = 22). Data from a subset within the community dwelling adults (n = 15) has been previously published (38). A, Bar and dot plots showing frequency of total muscle fibers expressing myosin heavy chain (MyHC) type 1, MyHC type 2a, or both MyHC 2a and MyHC 2x (2a/x hybrids). B, Mean fiber cross-sectional area (CSA) measured using MyoVision (39). C, Fiber type specific (type 1, type 2a, or type 2a/x) CSA. Data are expressed as mean ± sd; p values determined by Mann-Whitney U test; *significance p ≤ 0.05.

Figure 3.

Altered mitochondrial activity across fiber types within COVID muscle compared with controls. A, Quantification of total muscle fibers with dark (high mitochondrial activity), intermediate, or light (low mitochondrial activity) succinate dehydrogenase (SDH) histochemistry. Quantification of SDH histochemistry within individual fiber types: (B) type 1, (C) type 2a, and (D) hybrid type 2a/x. Quantification within vastus lateralis muscle biopsies from COVID patients (n = 9) or controls (n = 20). Data are expressed as mean ± sd; p values determined by Mann-Whitney U test; *significance p ≤ 0.05.

Figure 4.

Muscle from survivors of critical COVID have reduced cytochrome c oxidase (CCO) activity but no change in citrate synthase (CS) compared with controls. A, Quantification of CCO activity per microgram of protein. B, Muscle CS activity per microgram of protein. C, Reduced CCO activity per CS activity. A–C, Measured using muscle homogenates from COVID patients (n = 10) vs. controls (n = 6). Data are expressed as mean ± sd; p values determined by Mann-Whitney U test; *significance p ≤ 0.05.