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TGF-β Pathway Inhibition Protectsthe Diaphragm From Sepsis-Induced Wasting and Weakness in Rat

Baptiste, Jude*; Tissier, Florine*,†; Dubourg, Audrey; Droguet, Michael*; Castel, Thomas*; Karelle, Léon*; Marie-Agnès, Giroux-Metges*,†; Pennec, Jean-Pierre*

doi: 10.1097/SHK.0000000000001393
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ABSTRACT Sepsis is a frequent complication in patients in intensive care units (ICU). Diaphragm weakness,one of the most common symptoms observed, can lead to weaning problemsduring mechanical ventilation. Over the last couple of years, members of thetransforming growth factor (TGF) β family,such as myostatin, activin A and TGF-β1,have beenreported to strongly trigger the activation of protein breakdown involved in muscle wasting. The aim of this study was to investigate the effect of TGF-βinhibitorLY364947on the diaphragm during chronic sepsis.

Rats were separated into four groups exposed to different experimental conditions: (i) Control group, (ii) Septic group, (iii) Septic group with inhibitor from day 0 (LY D0), and (iv) Septic group with inhibitor from day 1 (LY D1). Sepsis was induced in ratsby cecal ligation and puncture, and carried out for seven days.

Chronic sepsis was responsible for a decrease inbody weight, food intake anddiaphragm's mass. The inhibitor was able to abolish diaphragm wasting only in the LY D1 group. Similarly, LY364947 had a beneficial effect on the diaphragm contraction only for the LY D1 group. SMAD3 was over-expressed and phosphorylated within rats in the Septic group;however this effect was reversed by LY364947. Calpain-1 and -2 as well as MAFbx were over-expressedwithin individuals in theSeptic group. Yet, calpain-1 and MAFbx expressions were decreased by LY364947

With this work, we demonstrate for the first time that the inhibition of TGF-β pathway during chronic sepsisprotects the diaphragm from wasting and weaknessas early asone day post infection. This could lead to more efficient treatment and care for septic patients in ICU.

*Laboratoire de Physiologie - EA 4324 ORPHY, IBSAM, Université de Bretagne Occidentale, Brest - France

Explorations Fonctionnelles Respiratoires, CHRU de Brest, Brest – France

CN Bio Innovations Ltd, Welwyn Garden City, AL7 3AX, UK

Address reprint requests to Jude Baptiste, PhD, Laboratoire de Physiologie – EA4324 ORPHY, Université de Bretagne Occidentale, 22 Avenue Camille Desmoulins 29238 Brest, Cedex 3 France; E-mail: bjude@outlook.fr

Received 14 September, 2018

Revised 15 October, 2018

Accepted 29 May, 2019

Highlights:

-Chronic sepsis of seven days is responsible for the decrease inthe diaphragm mass and its contractile force.

-Sepsis induces the activation of TGF-β signaling and proteolytic pathway in the diaphragm.

-The inhibition of TGF-β pathway prevents diaphragm dysfunction only if the inhibition starts 24 h after sepsis induction.

-The early inhibition of the TGF-β pathway does not protect the diaphragm during sepsis.

Conflict of interest: The authors declare that no conflict of interest exists.

© 2019 by the Shock Society