Autophagy ablation in skeletal muscles worsens sepsis-induced muscle wasting, impairs whole-body metabolism, and decreases survival

Jean-Philippe Leduc-Gaudet; Kayla Miguez; Marina Cefis; Julie Faitg; Alaa Moamer; Tomer Jordi Chaffer; Olivier Reynaud; Felipe E Broering; Anwar Shams; Dominique Mayaki; Laurent Huck; Marco Sandri; Gilles Gouspillou; Sabah N A Hussain

doi:10.1016/j.isci.2023.107475

Autophagy ablation in skeletal muscles worsens sepsis-induced muscle wasting, impairs whole-body metabolism, and decreases survival

iScience. 2023 Jul 25;26(8):107475. doi: 10.1016/j.isci.2023.107475. eCollection 2023 Aug 18.

Authors

Jean-Philippe Leduc-Gaudet^{1

2

3

4}, Kayla Miguez^{2

3}, Marina Cefis^{3

4}, Julie Faitg^{4

5}, Alaa Moamer³, Tomer Jordi Chaffer^{2

3}, Olivier Reynaud⁴, Felipe E Broering^{2

3}, Anwar Shams⁶, Dominique Mayaki^{2

3}, Laurent Huck^{2

3}, Marco Sandri^{3

7}, Gilles Gouspillou^{3

4}, Sabah N A Hussain^{2

3}

Affiliations

¹ Research Group in Cellular Signaling, Department of Medical Biology, Université du Québec À Trois-Rivières, Trois-Rivières, QC G9A 5H7, Canada.
² Department of Critical Care and Translational Research in Respiratory Diseases Program, Research Institute of the McGill University Health Centre (MUHC), Montréal, QC H3H 2R9, Canada.
³ Meakins-Christie Laboratories, Department of Medicine, Faculty of Medicine, McGill University, Montréal, QC H4A 3J1, Canada.
⁴ Département des sciences de l'activité physique, Faculté des sciences, Université du Québec à Montréal (UQAM), Montréal, QC H2X 1Y4, Canada.
⁵ Amazentis SA, EPFL Innovation Park, 1015 Lausanne, Switzerland.
⁶ Department of Pharmacology, Faculty of Medicine, Taif University, P.O.BOX 11099, Taif 21944, Saudi Arabia.
⁷ Veneto Institute of Molecular Medicine (VIMM) and Department of Biomedical Science, Università di Padova, 35129 Padova, Italy.

Abstract

Septic patients frequently develop skeletal muscle wasting and weakness, resulting in severe clinical consequences and adverse outcomes. Sepsis triggers sustained induction of autophagy, a key cellular degradative pathway, in skeletal muscles. However, the impact of enhanced autophagy on sepsis-induced muscle dysfunction remains unclear. Using an inducible and muscle-specific Atg7 knockout mouse model (Atg7^iSkM-KO), we investigated the functional importance of skeletal muscle autophagy in sepsis using the cecal ligation and puncture model. Atg7^iSkM-KO mice exhibited a more severe phenotype in response to sepsis, marked by severe muscle wasting, hypoglycemia, higher ketone levels, and a decreased in survival as compared to mice with intact Atg7. Sepsis and Atg7 deletion resulted in the accumulation of mitochondrial dysfunction, although sepsis did not further worsen mitochondrial dysfunction in Atg7^iSkM-KO mice. Overall, our study demonstrates that autophagy inactivation in skeletal muscles triggers significant worsening of sepsis-induced muscle and metabolic dysfunctions and negatively impacts survival.

Keywords: Genetics; Human metabolism; Musculoskeletal medicine.