Micro-environment Involvement in Muscle Alteration Induced (MicAMI-BPCO)

Micro-environment Involvement in Muscle Alteration Induced by Copd Exacerbation

Chronic Obstructive Pulmonary Disease (COPD) is characterized by persistent airway obstruction and inflammatory response of the lungs and bronchi. Episodes of exacerbations contribute to increase the severity and prognosis of the disease. Muscle dysfunction (loss of strengh and muscle mass) is one of comorbidities affecting 30% to 60% of patients and playing a key role in their prognosis. During exacerbation, some studies have suggested an association between muscle dysfunction and modifications of inflammatory circulating factors such as CRP, TNF-alpha, IL- 6, IL8, but no exhaustive study has identified precisely one (or more) biomarker(s) that can induce this muscle wasting during the exacerbation of COPD. Our hypothesis is that the serum of exacerbated COPD patients represents a deleterious microenvironment for the muscle cells which would amplify the mechanisms of atrophy linked to hospitalization. Our team has already developed a cell culture model to study the effects of the plasma microenvironment on atrophy of cultured myotubes. The investigators have shown that the serum of COPD patients can induce muscle atrophy.

The objectives of this study are : 1/ to evaluate the effects of circulating pro-inflammatory factors on atrophy and the myogenic capacities of muscle cells; and 2/ to identify one (or more) circulating biomarker (s) that may be responsible for the muscle damage induced by the microenvironment of hospitalized patients for exacerbation of COPD. First, myotubes and myoblasts of healthy subjects will be cultivated with 9 exacerbation copd patient serum or 9 copd patient serum or 9 healthy subject serum. Myotube diameters, atrophy, inflammatory and oxidative stress markers and alteration of the myogenic capacity of satellite cells will be compared between three groups. Second, the differential expression of circulating proinflammatory molecules will be compared in the serum of the three groups. Identifying circulating factors associated with muscle weakness is a necessary step to better understand the mechanisms and consider a personalized therapeutic approach that can improve the functional and clinical prognosis of disease.

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Study Overview

• Status: Completed
• Conditions: Chronic Obstructive Pulmonary Disease; Exacerbations; Skeletal Muscle Atrophy

• Study Type: Observational
• Enrollment (Actual): 27

Contacts and Locations

Study Locations

• France
  • Montpellier, France, 34295
    • Uhmontpellier

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

COPD patients hospitalized for exacerbation in Montpellier university hospital, France.

COPD patients recruited in Clinique du Souffle, La Vallonie, Lodève, France. Healthy volunteer subject recruited in Clinique du Souffle, La Vallonie, Lodève, France.

Description

Inclusion criteria 1/ for COPD patients hospitalized for exacerbation:

• Hospitalization for COPD exacerbation 2/ for COPD patients
• COPD patients GOLD II à IV
• Not having followed respiratory réhabilitation stay for at least one year 3/ for Healthy subjects
• healthy and sedentary (Voorips score <9)

Exclusion criteria:

1. for COPD patients hospitalized for exacerbation:

   • concomitant acute cardiac évent
   • trachéal intubation with mechanical ventilation
   • chronic respiratory disease other than COPD
   • locomotor, neurologic or psychiatric comorbidities

2. for COPD patients

   • Exacerbation with récent hospitalization (<4 weeks)
   • Neurologic comorbidity
3. for Healthy subjects - long term drug treatment with proven central effects

Study Plan

How is the study designed?

Design Details

• Observational Models: Other
• Time Perspectives: Retrospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Healthy subject
Stable COPD patients
Exacerbation COPD patients

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effects evaluation of circulating pro-inflammatory factors on atrophy	Atrophy marker evaluation in cultured muscle cells (myotubes); cultured myotube diameter exposed to the three serum groups (immunofluorescence); atrophy (ubiquitin proteasome system, proteolytic autophagy pathway), inflammatory (TNF-alpha, IL-6, IL-8…) and oxidative stress (ROS, lipid peroxidation) markers expressed by cells exposed to the three serum groups (PCR et WesternBlot)	6 months
Effects evaluation of circulating pro-inflammatory factors on the myogenic capacities of muscle cells	Myogenic capacities of cultured muscle cells (myoblastes); inflammatory (TNF-alpha, IL-6, IL-8…) and oxidative stress (ROS, lipid peroxidation) markers expressed by cells exposed to the three serum groups (PCR et WesternBlot); regeneration markers (Notch and myogenesis signaling pathways) expressed by cells exposed to the three serum groups (PCR et WesternBlot)	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identification of one (or more) circulating biomarker (s)	Identification of one (or more) circulating biomarker (s) that may be responsible for the muscle alteration induced by the microenvironment of patient in exacerbation of COPD	3 months

Collaborators and Investigators

• Sponsor: University Hospital, Montpellier
• Collaborators: APARD Fonds de dotation
• Investigators: Study Director: Maurice HAYOT, MD, PhD, University Hospital, Montpellier

Publications and helpful links

General Publications

• Spruit MA, Gosselink R, Troosters T, Kasran A, Gayan-Ramirez G, Bogaerts P, Bouillon R, Decramer M. Muscle force during an acute exacerbation in hospitalised patients with COPD and its relationship with CXCL8 and IGF-I. Thorax. 2003 Sep;58(9):752-6. doi: 10.1136/thorax.58.9.752.
• Crul T, Testelmans D, Spruit MA, Troosters T, Gosselink R, Geeraerts I, Decramer M, Gayan-Ramirez G. Gene expression profiling in vastus lateralis muscle during an acute exacerbation of COPD. Cell Physiol Biochem. 2010;25(4-5):491-500. doi: 10.1159/000303054. Epub 2010 Mar 23.
• Crul T, Spruit MA, Gayan-Ramirez G, Quarck R, Gosselink R, Troosters T, Pitta F, Decramer M. Markers of inflammation and disuse in vastus lateralis of chronic obstructive pulmonary disease patients. Eur J Clin Invest. 2007 Nov;37(11):897-904. doi: 10.1111/j.1365-2362.2007.01867.x. Epub 2007 Sep 20.
• Catteau M, Gouzi F, Blervaque L, Passerieux E, Blaquiere M, Ayoub B, Bughin F, Mercier J, Hayot M, Pomies P. Effects of a human microenvironment on the differentiation of human myoblasts. Biochem Biophys Res Commun. 2020 May 14;525(4):968-973. doi: 10.1016/j.bbrc.2020.03.020. Epub 2020 Mar 12.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2020
• Primary Completion (Actual): May 1, 2020
• Study Completion (Actual): May 30, 2020

Study Registration Dates

• First Submitted: June 15, 2020
• First Submitted That Met QC Criteria: June 22, 2020
• First Posted (Actual): June 26, 2020

Study Record Updates

• Last Update Posted (Actual): June 26, 2020
• Last Update Submitted That Met QC Criteria: June 22, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: Oxidative stress; Inflammation; Biomarkers; Muscle atrophy; COPD Exacerbation
• Additional Relevant MeSH Terms: Nervous System Diseases; Respiratory Tract Diseases; Lung Diseases; Neurologic Manifestations; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Muscular Atrophy; Atrophy
• Other Study ID Numbers: RECHMPL20_0137

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: NC

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No