Protective role of Parkin in skeletal muscle contractile and mitochondrial function

Abstract

Parkin is an E3 ubiquitin ligase encoded by the Park2 gene. Parkin has been implicated in the regulation of mitophagy, a quality control process in which defective mitochondria are sequestered in autophagosomes and delivered to lysosomes for degradation. Although Parkin has been mainly studied for its implication in neuronal degeneration in Parkinson disease, its role in other tissues remains largely unknown. In the present study, we investigated the skeletal muscles of Park2 knockout (Park2 ) mice to test the hypothesis that Parkin plays a physiological role in mitochondrial quality control in normal skeletal muscle, a tissue highly reliant on mitochondrial content and function. We first show that the tibialis anterior (TA) of Park2 mice display a slight but significant decrease in its specific force. Park2 muscles also show a trend for type IIB fibre hypertrophy without alteration in muscle fibre type proportion. Compared to Park2 muscles, the mitochondrial function of Park2 skeletal muscles was significantly impaired, as indicated by the significant decrease in ADP-stimulated mitochondrial respiratory rates, uncoupling, reduced activities of respiratory chain complexes containing mitochondrial DNA (mtDNA)-encoded subunits and increased susceptibility to opening of the permeability transition pore. Muscles of Park2 mice also displayed a decrease in the content of the mitochondrial pro-fusion protein Mfn2 and an increase in the pro-fission protein Drp1 suggesting an increase in mitochondrial fragmentation. Finally, Park2 ablation resulted in an increase in basal autophagic flux in skeletal muscles. Overall, the results of the present study demonstrate that Parkin plays a protective role in the maintenance of normal mitochondrial and contractile functions in normal skeletal muscles.

Guardian of mitochondrial function: an expanded role of Parkin in skeletal muscle

“…Despite the long‐standing idea that mitochondrial content and mitochondrial respiratory function change simultaneously, results from the present study (Gouspillou et al . ) confirm recent findings that this is not always the case (Granata et al . ).…”

“…Gouspillou et al . () report that despite a decrease in mitochondrial respiratory function in Park2 −/− mice, there was no change in mitochondrial content (indirectly assessed using citrate synthase activity, which has previously been reported to correlate with mitochondrial volume density). There was also a dissociation between the effects of Parkin on changes in mRNA and protein.…”

“…A recent study published in The Journal of Physiology by Gouspillou et al . () advances our understanding of the role of Parkin in the regulation of skeletal muscle mitochondrial content and respiratory function. Using Park2 −/− mice, Gouspillou et al .…”

“…While no difference was seen in maximal ADP‐stimulated mitochondrial respiration through complex I+II (CI+II P ), Gouspillou et al . () observed that maximal ADP‐stimulated mitochondrial respiration through complex I (CI P ) and complex IV (CIV P ) was 48% and 34% lower, respectively, in permeabilised gastrocnemius muscle fibres of Park2 −/− mice. Similarly, a 52% reduction in the acceptor control ratio was observed, and enzymatic activity of complexes I and IV was also lower, in Park2 −/− mice.…”

“…The study of Gouspillou et al . () adds to the repertoire of functions of Parkin by indicating its role in the maintenance of mitochondrial respiratory function in skeletal muscle, and possibly also the quality control of complexes containing a larger number of mtDNA‐encoded subunits (complex I and complex IV contain 7 and 3 mtDNA‐encoded subunits, respectively). How Parkin carries out the selective turnover of particular respiratory complex subunits, whether it only affects mtDNA‐encoded subunits, or if it specifically affects certain respiratory complexes (i.e.…”