Parkin Overexpression Attenuates Sepsis-Induced Muscle Wasting

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.

Mitochondrial Dysfunction Is a Common Denominator Linking Skeletal Muscle Wasting Due to Disease, Aging, and Prolonged Inactivity

“…Hence, bioenergetics failure was implicated to contribute to the severity of sepsis-induced muscle wasting [ 162 ]. Indeed, numerous reports have demonstrated the extensive mitochondrial dysfunction that occurs with sepsis-induced muscle wasting [ 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 ]. Mitochondrial dysfunction has been postulated to contribute to sepsis-induced muscle wasting in three ways: (1) diminished energy producing capacity; (2) increased oxidative stress; and (3) deficient satellite cell function.…”

“…In regard to the direct evidence implicating mitochondrial dysfunction as a critical mediator of sepsis-induced muscle wasting, a recent report reveals that overexpression of parkin, a protein responsible for mitophagy (i.e., mitochondrial autophagy), protects muscle against sepsis-induced wasting [ 168 ]. Mitochondria are observed to present a swollen appearance and disorganized morphology in muscle during sepsis [ 165 , 168 , 170 , 176 , 183 ]. However, parkin overexpression during sepsis attenuated altered mitochondrial morphology and prevented myofiber atrophy [ 168 ].…”

Ubiquitin Ligases at the Heart of Skeletal Muscle Atrophy Control

“…In addition, these loss-of-function studies also highlighted that PARKIN-mediated mitochondrial clearance contributes to proteasome activation during denervation in atrophied slow-twitch muscles [ 253 ]. On the flip side, gain-of-function studies showed that PARKIN overexpression in mice: (i) attenuates the ageing-related and the sepsis-induced muscle wasting and causes hypertrophy in adult skeletal muscle, (ii) increases mitochondrial content and enzymatic activities and (iii) protects from ageing-related increases of oxidative stress markers, fibrosis and apoptosis [ 185 , 186 ]. It is very likely that this role of PARKIN in controlling muscle mass has been evolutionary conserved.…”

Regulatory Roles of PINK1-Parkin and AMPK in Ubiquitin-Dependent Skeletal Muscle Mitophagy

“…However, the abundance of a protein does not reflect its enzymatic activity. Furthermore, in models of aging ( Leduc-Gaudet et al, 2019 ) and sepsis ( Leduc-Gaudet et al, 2020 ), skeletal muscle Parkin overexpression has been shown to attenuate morphological and functional mitochondrial defects, possibly through enhanced mitophagy. These studies suggest that Parkin activation is sufficient to induce mitophagy in skeletal muscle.…”