Dysfunctions of Human Muscle Stem Cells in Sepsis (DISCUSS)

Severe critical illness is often complicated by Intensive Care Unit - Acquired Weakness (ICU-AW), which is associated with increased in and post-ICU mortality, with delayed weaning from mechanical ventilation and with long-term functional. Several mechanisms have been incriminated in the pathophysiology of ICU-AW, but muscle regeneration has not been well investigated in this context, even though its involvement is suggested by the protracted functional consequences of ICU-AW. Recent data suggest that muscle regeneration could be impaired after sepsis, and that Mesenchymal Stem Cells (MSCs) treatment could improve the post-injury muscle recovery.

Study Overview

• Status: Completed
• Conditions: Sepsis
• Intervention / Treatment: Procedure: Human biological samples

Detailed Description

Severe critical illness is often complicated by Intensive Care Unit - Acquired Weakness (ICU-AW), which is clinically characterized by bilateral and symmetrical limb weakness and is related to a myopathy and/or axonal polyneuropathy. ICU-AW affects between 25% to 60% mechanically ventilated patients more than 7 days and is associated with increased in and post-ICU mortality, with delayed weaning from mechanical ventilation and with long-term functional disability. Most patients who develop an ICU-AW have been admitted for a sepsis episode and the main risk factors of ICU-AW include the severity of critical illness, immobilization, hyperglycemia and the use of some medications including steroids and neuromuscular agents, although this is somewhat controversial.

The pathophysiology of critical illness myopathy is thought to involve the following mechanisms: 1) impairment of muscular membrane excitability, secondary to an dysregulation of sodium channel gating, 2) mitochondrial dysfunction leading to bioenergetic failure and oxidative stress and 3) proteolysis, mainly related an activation of the ubiquitin-proteasome pathway. These mechanisms can be triggered by various factors, notably systemic inflammatory mediators, endocrine dysfunction, immobilization, some drugs and electrolyte disturbances. The protracted functional consequences of ICU-AW indicate that muscle regeneration is also impaired. Surprisingly, muscle regeneration, which essentially depends on the muscle stem cells (also called satellite cells), has not been well investigated in the context of critical illness. The satellite cells (SC), that are located at the periphery of the muscle fiber, are activated in response to any muscle injury and then proliferate and differentiate to repair or replace the damaged fibers, but also self-renew to replenish the muscle stem cells reservoir.

It was recently demonstrated in a murine model of polymicrobial peritonitis that SC activation, proliferation and expression of myogenic markers were impaired after sepsis, leading to an impaired muscle regeneration, but that post-sepsis intramuscular administration of exogenous Mesenchymal Stem Cells (MSCs) could reverse this SC dysfunction. MSC treatment significantly improved the post-injury muscle recovery with decreasing necrosis and fibrosis but also increased the force of isolated single fibers.

The objectives of this translational research are to identify the mechanisms of Human SC dysfunction in patients with severe sepsis, to describe in vitro the effects of MSCs on this SC dysfunction, and to study hematopoietic cells and their damage in the blood and muscle consecutively to a sepsis, and their interaction with muscle stem cells.

• Study Type: Interventional
• Enrollment (Actual): 93
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Créteil, France, 94010
    • Hopital Henri Mondor, Service de Réanimation chirurgicale polyvalente
  • Paris, France, 75013
    • Hôpital Pitié Salpétrière, Salle de surveillance post-interventionnelle, Accueil des Polytraumatisés
  • Paris, France, 75013
    • Hôpital Pitié Salpêtrière, Anesthésie et Réanimation, Institut de Cardiologie
  • Paris, France, 75013
    • Hôpital Pitié Salpêtrière, Service de Chirurgie Générale, Viscérale et Endocrinienne
  • Paris, France, 75013
    • Hôpital Pitié Salpêtrière, Service de Chirurgie Hépatobiliaire et de Transplantation Hépatique
  • Paris, France, 75013
    • Hôpital Pitié Salpêtrière, Service de réanimation chirurgicale polyvalente
  • Paris, France
    • Hôpital Saint-Antoine, Département d'Anesthésie-réanimation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Affiliated or beneficiary of a social security system
• Informed consent to research :

Consent from patient, Or consent from patient and close relative, Or non-objection from family for biological sample donation for research.

• Population 1 (sepsis) : Patients hospitalized in Intensive Care Unit, with intra-abdominal sepsis requiring emergency surgery.
• Population 2 (inflammatory condition with or without sepsis) : Brain dead patients scheduled for multi organ retrieval (2a) ; Patients with refractory cariogenic shock and requiring surgery for assistance with (2b).
• Population 3 (control) : Patients scheduled for intra-abdominal surgery.

Exclusion Criteria:

• Patient with preexisting neuromuscular disease
• Under 18 year-old
• Pregnancy..

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Patients with and without sepsis; Patients with sepsis, Patients with inflammatory disease without sepsis, Patients without inflammatory disease without sepsis. Human biological samples collected for research : Blood sample; Muscle biopsy; Bone marrow sample (mesenchymal stem cells)	Procedure: Human biological samples; Blood sample - Muscle biopsy - Bone marrow sample (mesenchymal stem cells)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Muscle regenerative capacities	The muscle regenerative capacity after sepsis would be assessed by the presence of anisocytosis, the proportion of small atrophic fibers, the proportion of endomysial fibrosis of the total muscle section area and the presence of calcified necrotic myofibers.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Satellite cell dysfunction after sepsis	Number of satellite cells (SC); Proportion of cells actively cycling; Capacity of SC to differentiate into myofibers	3 years
Regenerative capacities of Human satellite cells in presence of mesenchymal stem cells	Number of satellite cells (SC); Proportion of cells actively cycling; Capacity of SC to differentiate into myofibers	3 years

Collaborators and Investigators

• Sponsor: Institut Pasteur
• Investigators: Study Director: Fabrice Chrétien, Institut Pasteur

Publications and helpful links

General Publications

• Rocheteau P, Chatre L, Briand D, Mebarki M, Jouvion G, Bardon J, Crochemore C, Serrani P, Lecci PP, Latil M, Matot B, Carlier PG, Latronico N, Huchet C, Lafoux A, Sharshar T, Ricchetti M, Chretien F. Sepsis induces long-term metabolic and mitochondrial muscle stem cell dysfunction amenable by mesenchymal stem cell therapy. Nat Commun. 2015 Dec 15;6:10145. doi: 10.1038/ncomms10145.
• Duceau B, Blatzer M, Bardon J, Chaze T, Giai Gianetto Q, Castelli F, Fenaille F, Duarte L, Lescot T, Tresallet C, Riou B, Matondo M, Langeron O, Rocheteau P, Chretien F, Bougle A. Using a multiomics approach to unravel a septic shock specific signature in skeletal muscle. Sci Rep. 2022 Nov 5;12(1):18776. doi: 10.1038/s41598-022-23544-8.

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 23, 2016
• Primary Completion (ACTUAL): June 28, 2018
• Study Completion (ACTUAL): June 28, 2018

Study Registration Dates

• First Submitted: May 18, 2016
• First Submitted That Met QC Criteria: May 30, 2016
• First Posted (ESTIMATE): June 3, 2016

Study Record Updates

• Last Update Posted (ACTUAL): November 1, 2019
• Last Update Submitted That Met QC Criteria: October 31, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: Intensive Care Unit - Acquired Weakness (ICU-AW)
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Toxemia
• Other Study ID Numbers: 2015-015; ID-RCB number : 2015-A01022-47 (OTHER: French national registration number of the study)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO