Protein recycling and limb muscle recovery after critical illness in slow- and fast-twitch limb muscle

Abstract

An impaired capacity of muscle to regenerate after critical illness results in long-term functional disability. We previously described in a long-term rat peritonitis model that gastrocnemius displays near-normal histology whereas soleus demonstrates a necrotizing phenotype. We thus investigated the link between the necrotizing phenotype of critical illness myopathy and proteasome activity in these two limb muscles. We studied male Wistar rats that underwent an intraperitoneal injection of the fungal cell wall constituent zymosan or n-saline as a sham-treated control. Rats ( n = 74) were killed at 2, 7, and 14 days postintervention with gastrocnemius and soleus muscle removed and studied ex vivo. Zymosan-treated animals displayed an initial reduction of body weight but a persistent decrease in mass of both lower hindlimb muscles. Zymosan increased chymotrypsin- and trypsin-like proteasome activities in gastrocnemius at days 2 and 7 but in soleus at day 2 only. Activated caspases-3 and -9, polyubiquitin proteins, and 14-kDa fragments of myofibrillar actin (proteasome substrates) remained persistently increased from day 2 to day 14 in soleus but not in gastrocnemius. These results suggest that a relative proteasome deficiency in soleus is associated with a necrotizing phenotype during long-term critical illness. Rescuing proteasome clearance may offer a potential therapeutic option to prevent long-term functional disability in critically ill patients.

The impact of hindlimb disuse on sepsis‐induced myopathy in mice

“…Oxidative muscles seem to be highly susceptible to abnormalities induced by sepsis. Preau et al have identified a necrotizing phenotype in SOL muscle of rats exposed to a model of peritonitis in contrast to the glycolytic gastrocnemius muscle, which did not display the necrotic phenotype (Preau et al, 2019). Owen et al (2019) demonstrated that sepsis, induced via cecal slurry injection, caused EDL weakness, but not atrophy.…”

“…It is reasonable to expect that accumulation of macrophages and other inflammatory cell populations would result in higher production of ROS. High ROS production is associated with halted protein synthesis and accelerated protein degradation due to enhanced proteasome proteolytic degradation and autophagy pathways (Callahan & Supinski, 2009; Powers et al, 2012; Preau et al, 2019; Wollersheim et al, 2014). Whether and when these pathways are upregulated over the course of the myopathy, in our double‐hit model, warrants further investigation.…”

Sepsis therapies: learning from 30 years of failure of translational research to propose new leads

“…Critically ill patients face multiple risk factors causing myopathies such as immobilization, local inflammation‐induced by systemic mediators, and nutritional defects (Friedrich et al , ). Mechanisms responsible for septic myopathy include sodium channel dysfunction with upregulation of non‐selective channels (Balboa et al , ), ubiquitin–proteasome pathway protein proteolysis, proteasome activation and increased autophagy (Wollersheim et al , ; Preau et al , ), changes in intracellular calcium levels leading to excitation‐contraction uncoupling (Batt et al , ), and mitochondrial derangements with an increase in free radical generation (Zolfaghari et al , ). Although autophagy is among the mechanisms of protein loss, its balanced activation can protect muscles from the accumulation of toxic proteins (Morel et al , ).…”

Cognitive Impairment and Dementia: Gaining Insight through Circadian Clock Gene Pathways

“…Autophagy as part of the programmed death pathways is linked to oxidative stress [5,16,54,73,[135][136][137][138][139][140]. Autophagy induction recycles cytoplasmic organelles and components for tissue remodeling [14,141] and can remove non-functional organelles [8, 73,136,142]. Macroautophagy recycles organelles in cells and sequesters cytoplasmic proteins into autophagosomes.…”