ROS-Drp1-mitophagy feedback loop regulates myogenic differentiation via actin cytoskeleton remodeling-mediated

Aiwen Jiang1, Luyao Wang1, Xinyu Liu1

  • 1Key Laboratory for Animal Genetics, Breeding, Reproduction and Molecular Design, College of Animal Science and Technology, Yangzhou University, Yangzhou, People's Republic of China.

Abstract

Insights

Dynamin-related protein 1 (Drp1) is crucial for muscle cell (myogenic) differentiation. This study reveals how Drp1, through a feedback loop involving reactive oxygen species (ROS) and mitophagy, regulates mitochondrial dynamics and actin remodeling essential for this process.

Area of Science:

  • Cell Biology
  • Mitochondrial Dynamics
  • Muscle Development

Background:

  • Mitochondrial division initiates myogenic differentiation.
  • The precise role of Dynamin-related protein 1 (Drp1) in myogenic differentiation remains unclear.

Purpose of the Study:

  • To elucidate the mechanism by which Drp1 regulates myogenic differentiation.
  • To investigate the interplay between Drp1, reactive oxygen species (ROS), mitophagy, and the actin cytoskeleton.

Main Methods:

  • Knockdown of Drp1 expression in C2C12 cells and mice using siRNA and AAV9-shDrp1.
  • Analysis of mitochondrial damage, ROS levels, myogenic differentiation markers, mitophagy, and the actin/MRTF-A/SRF pathway via qPCR, Western blotting, immunofluorescence, and flow cytometry.

Main Results:

  • Drp1 expression increases during C2C12 cell differentiation, and its knockdown impairs myotube formation.
  • A feedback loop exists where ROS activate Drp1, which in turn reduces ROS by promoting mitophagy.
  • Drp1 knockdown disrupts ROS homeostasis, affecting actin dynamics and blocking MRTF-A nuclear translocation, thus hindering myogenic differentiation.

Conclusions:

  • This study reveals the functional mechanism of Drp1 in myogenic differentiation.
  • Clarified the interactions among ROS, Drp1-mediated mitophagy, and actin cytoskeleton remodeling during muscle development.

Related Concept Videos

Master Transcription Regulators02:23

Master Transcription Regulators

Master transcription regulators are regulatory proteins that are predominantly responsible for regulating the expression of multiple genes. Often these genes work in concert to drive a  complex process. Activation of a master transcription regulator can lead to a cascade of transcriptional activation necessary for that outcome. These regulators can directly bind to the regulatory sequences of the various genes involved, or they can indirectly regulate transcription by binding to regulatory...
7.1K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
4.0K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.9K
Formation of Muscle Fibers from Myoblasts01:13

Formation of Muscle Fibers from Myoblasts

De novo myogenesis, or the formation of muscle fibers, begins during the early embryonic stages. The skeletal muscle is formed from somites– blocks of embryonic cell layers. The somites are further divided into dermatomes, myotomes, sclerotomes, and syndetomes. Among these, the myotomes give rise to muscle fibers.
Muscle progenitor cells (MPCs) are formed from the myotomes. MPCs express genes that encode the transcription factors Pax3 and Pax7. Along with Pax 3/7, other transcription...
5.2K
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
6.1K
TGF - β Signaling Pathway01:16

TGF - β Signaling Pathway

The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors...
7.7K