Muscle stem cells contribute to long‐term tissue repletion following surgical sepsis

Abstract

Background Over the past decade, advances in sepsis identification and management have resulted in decreased sepsis mortality. This increase in survivorship has highlighted a new clinical obstacle: chronic critical illness (CCI), for which there are no effective treatment options. Up to half of sepsis survivors suffer from CCI, which can include multi-organ dysfunction, chronic inflammation, muscle wasting, physical and mental disabilities, and enhanced frailty. These symptoms prevent survivors from returning to regular day-to-day activities and are directly associated with poor quality of life. Methods Mice were subjected to cecal ligation and puncture (CLP) with daily chronic stress (DCS) as an in vivo model to study sepsis late-effects/sequelae on skeletal muscle components. Longitudinal monitoring was performed via magnetic resonance imaging, skeletal muscle and/or muscle stem cell (MuSCs) assays (e.g., post-necropsy wet muscle weights, minimum Feret diameter measurements, in vitro MuSC proliferation and differentiation, number of regenerating myofibres and numbers of Pax7-positive nuclei per myofibre), post-sepsis whole muscle metabolomics and MuSC isolation and high-content transcriptional profiling. Results We report several findings supporting the hypothesis that MuSCs/muscle regeneration are critically involved in post-sepsis muscle recovery. First, we show that genetic ablation of muscle stem cells (MuSCs) impairs post-sepsis muscle recovery (maintenance of 5-8% average lean mass loss compared with controls). Second, we observe impaired MuSCs expansion capacity and morphological defects at 26 days post-sepsis compared with control MuSCs (P < 0.001). Third, when subjected to an experimental muscle injury, sepsis-recovered mice exhibited evidence of impaired muscle regeneration compared with non-septic mice receiving the same muscle injury (CLP/DCS injured mean minimum Feret is 92.1% of control injured, P < 0.01). Fourth, we performed a longitudinal RNA sequencing study on MuSCs isolated from post-sepsis mice and found clear transcriptional differences in all post-sepsis samples compared with controls. At Day 28, CLP/DCS mice satellite cells have multiple altered metabolic pathways, such as oxidative phosphorylation, mitochondrial dysfunction, sirtuin signalling and oestrogen receptor signalling, compared with controls (P < 0.001). Conclusions Our data show that MuSCs and muscle regeneration are required for effective post-sepsis muscle recovery and that sepsis triggers morphological, functional, and transcriptional changes in MuSCs. Moving forward, we strive to leverage a more complete understanding of post-sepsis MuSC/regenerative defects to identify and test novel therapies that promote muscle recovery and improve quality of life in sepsis survivors.

A TGF-β/KLF10 signaling axis regulates atrophy-associated genes to induce muscle wasting in pancreatic cancer

“…After fixing with 4% PFA as mentioned above, TA sections were stained to assess the presence of different MHC isoforms, and thus myofiber types, as previously described ( 41 ). Briefly, sections were incubated with BA-D5 (type I myofibers, supernatant, 1:100, DSHB), SC-71 (type IIa myofibers, supernatant, 1:100, DSHB), BF-F3 (type IIb myofibers, concentrate, 1:100, DSHB), and laminin (1:250, Sigma) diluted in 1% Bovine Serum Albumin (BSA).…”

Predictive Value of Soluble Programmed Cell Death Ligand-1 in the Progression of Septic Patients to Chronic Critical Illness in the Intensive Care Unit: A Prospective Observational Clinical Study

“…Early recognition, bundle treatment, and organ function support have culminated in a dramatic decrease in in-hospital mortality, with nearly half of septic patients surviving the hyperinflammatory phase. However, one-third of septic patients still experience progression to chronic critical illness (CCI), which is characterized by prolonged hospitalization, cognitive dysfunction, and poor quality of life (3,4). Chronic critical illness patients are regularly associated with immune dysfunction and susceptibility to secondary infections compared with patients with immune homeostasis and rapid recovery (RAP), with rehospitalization occurring in more than 50% of cases and defining a small but medically costly group (5,6).…”

Understanding Post-Sepsis Syndrome: How Can Clinicians Help?

“…In addition to the detrimental effect of bed rest and muscle disuse on muscle mass, 97 sepsis-induced skeletal muscle catabolism reflects impaired satellite cell and mitochondrial functions, increased proteolysis, decreased protein synthesis and release of degradation products that have pro-inflammatory features as damage-associated molecular patterns (DAMPs) from skeletal muscle mitochondria. 30 , 96 , 98 , 99 Satellite cells are the muscle stem cells and a proper function is essential for muscle repair in response to factors such as injury and exercise. 30 When activated, satellite cells turn from the quiescent state to start forming myotubes.…”

“… 30 Satellite cells are required for maintenance of lean mass as demonstrated in a mouse model of sepsis, but its function declines in response to sepsis. 30 , 99 Transcriptomic changes of satellite cells induced by sepsis in mice were persistently changed at day 28 after sepsis compared to control, reflecting impaired energetic pathways representing oxidative phosphorylation and mitochondrial dysfunction. These observations reflect impaired satellite cell function and reduced muscle repair.…”

“…These observations reflect impaired satellite cell function and reduced muscle repair. 99 The detrimental effect of mitochondrial and satellite cell dysfunctions on the maintenance of muscle energetics and repair warrant further research to develop strategies to target sepsis-induced muscle catabolism state with relevance to prevent muscle loss and functional decline after sepsis.…”