Lack of compensatory mitophagy in skeletal muscles during sepsis

Sami Sedraoui; Jean-Philippe Leduc-Gaudet; Dominique Mayaki; Alaa Moamer; Laurent Huck; Gilles Gouspillou; Basil J Petrof; Sabah Hussain

doi:10.1113/JP286216

Lack of compensatory mitophagy in skeletal muscles during sepsis

J Physiol. 2024 May 15. doi: 10.1113/JP286216. Online ahead of print.

Authors

Sami Sedraoui^{1

2}, Jean-Philippe Leduc-Gaudet³, Dominique Mayaki^{1

2}, Alaa Moamer^{1

2}, Laurent Huck^{1

2}, Gilles Gouspillou⁴, Basil J Petrof^{1

2}, Sabah Hussain^{1

2

5}

Affiliations

¹ Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, QC, Canada.
² Translational Research in Respiratory Diseases Program, Research Institute of the McGill University Health Centre, Montral, QC, Canada.
³ Department of Medical Biology, Faculty of Health Sciences, Université du Québec à Trois-Rivieres, Trois-Rivieres, QC, Canada.
⁴ Département des Sciences de l'Activité Physique, Faculté des Sciences, Université du Québec à Montréal, Montréal, QC, Canada.
⁵ Department of Critical Care Medicine, McGill University Health Centre, Montreal, QC, Canada.

PMID: 38748778
DOI: 10.1113/JP286216

Abstract

Skeletal muscle dysfunction is a major problem in critically ill patients suffering from sepsis. This condition is associated with mitochondrial dysfunction and increased autophagy in skeletal muscles. Autophagy is a proteolytic mechanism involved in eliminating dysfunctional cellular components, including mitochondria. The latter process, referred to as mitophagy, is essential for maintaining mitochondrial quality and skeletal muscle health. Recently, a fluorescent reporter system called mito-QC (i.e. mitochondrial quality control) was developed to specifically quantify mitophagy levels. In the present study, we used mito-QC transgenic mice and confocal microscopy to morphologically monitor mitophagy levels during sepsis. To induce sepsis, Mito-QC mice received Escherichia coli lipopolysaccharide (10 mg kg^-1 i.p.) or phosphate-buffered saline and skeletal muscles (hindlimb and diaphragm) were excised 48 h later. In control groups, there was a negative correlation between the basal mitophagy level and overall muscle mitochondrial content. Sepsis increased general autophagy in both limb muscles and diaphragm but had no effect on mitophagy levels. Sepsis was associated with a downregulation of certain mitophagy receptors (Fundc1, Bcl2L13, Fkbp8 and Phbb2). The present study suggests that general autophagy and mitophagy can be dissociated from one another, and that the characteristic accumulation of damaged mitochondria in skeletal muscles under the condition of sepsis may reflect a failure of adequate compensatory mitophagy. KEY POINTS: There was a negative correlation between the basal level of skeletal muscle mitophagy and the mitochondrial content of individual muscles. Mitophagy levels in limb muscles and the diaphragm were unaffected by lipopolysaccharide (LPS)-induced sepsis. With the exception of BNIP3 in sepsis, LPS administration induced either no change or a downregulation of mitophagy receptors in skeletal muscles.

Keywords: autophagy; mitochondria; mitophagy; mito‐QC; sepsis; skeletal muscles.

Abstract

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