Loss of Parkin impairs mitochondrial function and leads to muscle atrophy

Abstract

Parkinson's disease is a neurodegenerative disease characterized by tremors, muscle stiffness, and muscle weakness. Molecular genetic analysis has confirmed that mutations in PARKIN and PINK1 genes, which play major roles in mitochondrial quality control and mitophagy, are frequently associated with Parkinson's disease. PARKIN is an E3 ubiquitin ligase that translocates to mitochondria during loss of mitochondrial membrane potential to increase mitophagy. Although muscle dysfunction is noted in Parkinson's disease, little is known about the involvement of PARKIN in the muscle phenotype of Parkinson's disease. In this study, we report that the mitochondrial uncoupler CCCP promotes PINK1/PARKIN-mediated mitophagy in myogenic C2C12 cells. As a result of this excess mitophagy, we show that CCCP treatment of myotubes leads to the development of myotube atrophy in vitro. Surprisingly, we also found that siRNA-mediated knockdown of Parkin results in impaired mitochondrial turnover. In addition, knockdown of Parkin led to myotubular atrophy in vitro. Consistent with these in vitro results, Parkin knockout muscles showed impaired mitochondrial function and smaller myofiber area, suggesting that Parkin function is required for post-natal skeletal muscle growth and development.

Protein composition of the muscle mitochondrial reticulum during postnatal development

“…In an in vitro study, siRNA‐mediated Parkin knockdown was shown to have considerably diminished protein levels of both MFN1/2 and Drp1 in C2C12 myoblasts (Peker et al . ) for which the initial differentiation process into myotubes requires the upregulation of autophagic proteins (Sin et al . ).…”

“…In a recent study, impaired Parkin led to dysregulated mitochondrial function, as well as smaller fibre size (Peker et al . ), suggesting that it has an essential role in muscle development. A loss of PINK1 and Parkin has also been recently associated with a strong inflammatory phenotype after exhaustive exercise in mice (Sliter et al .…”

Hemiparkinsonism or Hemidystonia With Hemiatrophy Syndrome: A Case Series With Follow-Up

“…Pramstaller presented one HPHA female patient with parkin mutations (Pramstaller et al, 2002). Peker found that the knockdown of the Parkin gene led to myotubular atrophy in vitro, an effect that was associated with impaired mitochondrial function and a smaller myofiber area (Peker et al, 2018). Consequently, the genetic etiology of HPHA and HDHA, which include parkin mutations, cannot be fully excluded.…”

Mitophagy in the Skeletal Muscle Is Suppressed in Spleen Qi Deficiency

“…ROS are highly reactive byproducts of mitochondrial respiration and their accumulation will impair cellular components and activate death pathways; however, cells initiate related mechanisms such as mitophagy to opposite ROS accumulation [10] [11] [12]. MMP is another byproduct of OXPHOS, and its reduction can activate PINK1-Parkin pathway to induce mitophagy [13] [14].…”