*Article* **Parkin Overexpression Attenuates Sepsis-Induced Muscle Wasting**

**Jean-Philippe Leduc-Gaudet 1,2,3,4,5, Dominique Mayaki 1, Olivier Reynaud 2,3,4,5, Felipe E. Broering 1,2, Tomer J. Cha**ff**er 1, Sabah N. A. Hussain 1,2,\*,**† **and Gilles Gouspillou 2,3,4,5,6,\*,**†


Received: 30 April 2020; Accepted: 8 June 2020; Published: 11 June 2020

**Abstract:** Sepsis elicits skeletal muscle weakness and fiber atrophy. The accumulation of injured mitochondria and depressed mitochondrial functions are considered as important triggers of sepsis-induced muscle atrophy. It is unclear whether mitochondrial dysfunctions in septic muscles are due to the inadequate activation of quality control processes. We hypothesized that overexpressing Parkin, a protein responsible for the recycling of dysfunctional mitochondria by the autophagy pathway (mitophagy), would confer protection against sepsis-induced muscle atrophy by improving mitochondrial quality and content. Parkin was overexpressed for four weeks in the limb muscles of four-week old mice using intramuscular injections of adeno-associated viruses (AAVs). The cecal ligation and perforation (CLP) procedure was used to induce sepsis. Sham operated animals were used as controls. All animals were studied for 48 h post CLP. Sepsis resulted in major body weight loss and myofiber atrophy. Parkin overexpression prevented myofiber atrophy in CLP mice. Quantitative two-dimensional transmission electron microscopy revealed that sepsis is associated with the accumulation of enlarged and complex mitochondria, an effect which was attenuated by Parkin overexpression. Parkin overexpression also prevented a sepsis-induced decrease in the content of mitochondrial subunits of NADH dehydrogenase and cytochrome C oxidase. We conclude that Parkin overexpression prevents sepsis-induced skeletal muscle atrophy, likely by improving mitochondrial quality and contents.

**Keywords:** muscle atrophy; septicemia; mitochondria; mitochondrial fusion; mitochondrial fission
