Leduc-Gaudet 2021 bioRxiv
Leduc-Gaudet JP, Miguez K, Marina Cefis M, Moamer A, Chaffer TJ, Faitg J, Reynaud O, Broering FE, Shams A, Mayaki D, Huck L, Sandri M, Gouspillou G, Hussain SNA (2021) Role of autophagy in sepsis-induced skeletal muscle dysfunction, whole-body metabolism, and survival. bioRxiv doi: https://doi.org/10.1101/2021.08.05.455081. |
Β» Open Access
Leduc-Gaudet Jean-Philippe, Miguez Kayla, Cefis Marina, Moamer Alaa, Chaffer Tomer Jordi, Faitg Julie, Reynaud Olivier, Broering Felipe E, Shams Anwar, Mayaki Dominique, Huck Laurent, Sandri Marco, Gouspillou Gilles, Hussain Sabah NA (2021) bioRxiv
Abstract: Septic patients frequently develop skeletal muscle wasting and weakness, resulting in severe clinical consequences and adverse outcomes. Autophagy is a stress-induced degradative process essential to cell survival. Recent studies have demonstrated that sepsis triggers sustained induction of autophagy in skeletal muscles, although the impact of this enhanced autophagy on sepsis-induced muscle dysfunction remains unclear. Atg7 is an autophagy gene that plays a major role in autophagosome formation. Using an inducible and muscle-specific Atg7 knockout mouse model (Atg7iSkM-KO), we investigated the functional importance of skeletal muscle autophagy in sepsis. Sepsis was induced using cecal ligation and perforation (CLP) with a sham operation serving as a control. Atg7iSkM-KO mice exhibited a more severe phenotype in response to sepsis, marked by severe muscle wasting and contractile dysfunction, hypoglycemia, higher ketone levels and a decreased in survival as compared to mice with intact Atg7. Several genes that encode 26S proteasome subunits were upregulated, suggesting that activation of the ubiquitin-proteasome system is responsible for the severe muscle atrophy that was seen in these mice. Sepsis and Atg7 deletion resulted in the accumulation of mitochondrial dysfunction, although sepsis did not further worsen mitochondrial dysfunction in Atg7iSkM-KO mice. Overall, our study demonstrates that autophagy inactivation in skeletal muscles triggers significant worsening of sepsis-induced contractile and metabolic dysfunctions and negatively impacts survival. Induction of autophagy in skeletal muscles in response to sepsis thus represents a protective mechanism. β’ Keywords: Autophagy, Sepsis, Skeletal muscle, Atrophy, Mitochondria, Proteasome β’ Bioblast editor: Plangger M β’ O2k-Network Lab: CA Montreal Gouspillou G
Labels: MiParea: Respiration, Genetic knockout;overexpression
Pathology: Sepsis
Organism: Mouse Tissue;cell: Skeletal muscle Preparation: Permeabilized tissue
Coupling state: LEAK, OXPHOS
Pathway: N
HRR: Oxygraph-2k
2021-10