Weak by the machines: muscle motor protein dysfunction – a side effect of intensive care unit treatment

Abstract

Intensive care interventions involve periods of mechanical ventilation, sedation and complete mechanical silencing of patients. Critical illness myopathy (CIM) is an ICU-acquired myopathy that is associated with limb muscle weakness, muscle atrophy, electrical silencing of muscle and motor proteinopathy. The hallmark of CIM is a preferential muscle myosin loss due to increased catabolic and reduced anabolic activity. The ubiquitin proteasome pathway plays an important role, apart from recently identified novel mechanisms affecting non-lysosomal protein degradation or autophagy. CIM is not reproduced by pure disuse atrophy, denervation atrophy, steroid-induced atrophy or septic myopathy, although combinations of high-dose steroids and denervation can mimic CIM. New animal models of critical illness and ICU treatment (i.e. mechanical ventilation and complete immobilization) provide novel insights regarding the time course of protein synthesis and degradation alterations, and the role of protective chaperone activities in the process of myosin loss. Altered mechano-signalling seems involved in triggering a major part of myosin loss in experimental CIM models, and passive loading of muscle potently ameliorates the CIM phenotype. We provide a systematic overview of similarities and distinct differences in the signalling pathways involved in triggering muscle atrophy in CIM and isolated trigger factors. As preferential myosin loss is mostly determined from biochemistry analyses providing no spatial resolution of myosin loss processes within myofibres, we also provide first results monitoring myosin signal intensities during experimental ICU intervention using multi-photon Second Harmonic Generation microscopy. Our results confirm that myosin loss is an evenly distributed process within myofibres rather than being confined to hot spots.

Electrical Stimulation Prevents Preferential Skeletal Muscle Myosin Loss in Steroid-Denervation Rats

“…Increased ROS/RNS has been shown to directly depress myofibrillar function in several pathophysiological conditions ( Supinski and Callahan, 2007 ). Moreover, oxidative modifications of cellular proteins markedly accelerates their rate of degradation by, e.g., activation of calpains ( Friedrich et al, 2018 ) and increases in the muscle-specific E3 ligases muscle ring finger-1 (MuRF-1) and atrogin-1, which are part of the ubiquitin-proteasome system ( Grune et al, 2003 ; Betters et al, 2004 ; Smuder et al, 2010 ; Powers et al, 2016 ). Signaling via the p38 mitogen-activated protein kinase (MAPK) pathway has been proposed to mediate oxidative stress-induced atrogin-1 expression and ubiquitin-conjugating activity in skeletal muscle ( Li et al, 2005 ; Jin and Li, 2007 ).…”

“…In the present study we used the steroid-denervation (S-D) rat model, where animals were exposed to a combination of a pharmacological glucocorticoid treatment and surgical denervation ( Rich et al, 1998 ; Kraner et al, 2011 ; Friedrich et al, 2018 ). Some S-D rats were exposed to daily ES treatment.…”

Maintenance of sarcomeric integrity in adult muscle cells crucially depends on Z-disc anchored titin

“…Interestingly, our conditional TTN KO-mouse model recapitulates key changes observed in the skeletal muscles of critically ill intensive care unit (ICU) patients with acute quadriplegic myopathy (critical illness myopathy (CIM) or myosinopathy), which is seen in up to~30% of ICU patients 26 . A hallmark of CIM is the preferential loss of myosin and myosin-associated proteins but not thin-filament proteins in the sarcomeres of proximal and distal skeletal muscles 27 .…”

BGP‐15: A potential therapeutic agent for critical illness myopathy

“…With the significant improvements in modern intensive care medicine, mortality of ICU patients has dropped; on the other hand, it increases incidence of muscle weakness and paralysis, typically referred to as critical illness myopathy (CIM). Triggering factors for CIM include sepsis, mechanical ventilation, muscle unloading, steroid treatment or denervation . CIM is marked by muscle atrophy, a preferential myosin loss, and reduction of electrical excitability.…”

“…During the past decade, Larsson and colleagues have significantly contributed to improve our understanding of the mechanism underlying CIM using unique experimental porcine and rodent ICU models that allow mechanical ventilation with pharmacological post‐synaptic neuromuscular blockade for several weeks . Altered mechano‐signalling seems involved in triggering a major part of selective myosin loss in experimental CIM models, and passive mechanical loading of the muscle partially ameliorates the CIM phenotype.…”