A prospective clinical study on the mechanisms underlying critical illness myopathy—A time‐course approach

Abstract

Background Critical illness myopathy (CIM) is a consequence of modern critical care resulting in general muscle wasting and paralyses of all limb and trunk muscles, resulting in prolonged weaning from the ventilator, intensive care unit (ICU) treatment and rehabilitation. CIM is associated with severe morbidity/mortality and significant negative socioeconomic consequences, which has become increasingly evident during the current COVID-19 pandemic, but underlying mechanisms remain elusive. Methods Ten neuro-ICU patients exposed to long-term controlled mechanical ventilation were followed with repeated muscle biopsies, electrophysiology and plasma collection three times per week for up to 12 days. Single muscle fibre contractile recordings were conducted on the first and final biopsy, and a multiomics approach was taken to analyse gene and protein expression in muscle and plasma at all collection time points. Results (i) A progressive preferential myosin loss, the hallmark of CIM, was observed in all neuro-ICU patients during the observation period (myosin:actin ratio decreased from 2.0 in the first to 0.9 in the final biopsy, P < 0.001). The myosin loss was coupled to a general transcriptional downregulation of myofibrillar proteins (P < 0.05; absolute fold change >2) and activation of protein degradation pathways (false discovery rate [FDR] <0.1), resulting in significant muscle fibre atrophy and loss in force generation capacity, which declined >65% during the 12 day observation period (muscle fibre cross-sectional area [CSA] and maximum single muscle fibre force normalized to CSA [specific force] declined 30% [P < 0.007] and 50% [P < 0.0001], respectively). (ii) Membrane excitability was not affected as indicated by the maintained compound muscle action potential amplitude upon supramaximal stimulation of upper and lower extremity motor nerves. (iii) Analyses of plasma revealed early activation of inflammatory and proinflammatory pathways (FDR < 0.1), as well as a redistribution of zinc ions from plasma. Conclusions The mechanical ventilation-induced lung injury with release of cytokines/chemokines and the complete mechanical silencing uniquely observed in immobilized ICU patients affecting skeletal muscle gene/protein expression are forwarded as the dominant factors triggering CIM.

Mitochondrial Dysfunction in Intensive Care Unit-Acquired Weakness and Critical Illness Myopathy: A Narrative Review

“…Muscle biopsies from critically ill patients revealed an overall decrease in mtDNA content and a downregulation of many genes orchestrating mitochondrial function [ 90 , 161 ]. This was also recently confirmed in patients with CIM [ 77 ]. Especially genes for mitochondrial fusion and replication, such as PGC1α, MFN2 and OPA1, seem to be affected in skeletal muscles [ 102 , 114 ].…”

“…Although the majority of studies were able to mimic certain pathophysiological aspects, it has been found that the combined effect and prolonged application of some methods was best suited to replicate predominant myosin loss, decreased compound muscle action potentials and normal nerve conduction velocities, similar to patients with CIM [ 69 , 74 , 75 ]. In this context, porcine animal models of critical illness revealed marked downregulations in mitochondrial gene expression controlling the PGC1-family, the ETC enzyme complexes and several metabolic pathways [ 73 , 76 ], matching at least in part with the results of patients with CIM [ 77 , 78 ]. Although not covering all methodical aspects of a fully grown ICU animal model, studies investigating mitochondrial function by pure immobilization [ 52 , 53 , 54 ], denervation [ 47 , 49 , 59 ] or sepsis [ 79 , 80 ] also show deficits in mitochondrial structure and function comparable to observations in critically ill patients, including mitochondrial swelling, decreased mitochondrial content and downregulation of PGC1α mRNA expression as well as several mitochondrial metabolic pathways [ 81 , 82 , 83 ].…”

“…Sepsis survivors showed marked increases in PGC1α mRNA and NRF1 mRNA expression compared to non-survivors, implying insufficient activation of mitochondrial biogenesis contributing to adverse outcomes in critical illness [ 89 ]. Within the first two weeks, mitochondrial dysfunction may be aggravated in prolonged critical illness and have insufficient regenerative capacities, as a further decline in mitochondrial content, gene expression (PGC1α, DRP1), metabolic activity (OXPHOS, β-oxidation) and biogenesis are immanent [ 77 , 78 , 90 ]. However, metabolic and respiratory activity might adapt after surviving critical illness, switching nutrient utilization of the remaining mitochondria to increased FFA oxidation.…”

SPSB1‐mediated inhibition of TGF‐β receptor‐II impairs myogenesis in inflammation

“…Septic patients often develop intensive care unit‐acquired weakness (ICUAW), which is accompanied by muscle‐mass loss, increased morbidity, and mortality 1,2 . ICUAW is defined as ‘clinically detected weakness in critically ill patients in whom there is no plausible aetiology other than critical illness’ 3 .…”

“…Septic patients often develop intensive care unit-acquired weakness (ICUAW), which is accompanied by muscle-mass loss, increased morbidity, and mortality. 1,2 ICUAW is defined as 'clinically detected weakness in critically ill patients in whom there is no plausible aetiology other than critical illness'. 3 Patients with ICUAW are classified into those with critical illness myopathy (CIM), critical illness polyneuropathy (CIP), or a combination of both.…”