Fatty acids impact sarcomere integrity through myristoylation and ER homeostasis

Cell Rep. 2021 Aug 17;36(7):109539. doi: 10.1016/j.celrep.2021.109539.

Abstract

Decreased ability to maintain tissue integrity is critically involved in aging and degenerative diseases. Fatty acid (FA) metabolism has a profound impact on animal development and tissue maintenance, but our understanding of the underlying mechanisms is limited. We investigated whether and how FA abundance affects muscle integrity using Caenorhabditis elegans. We show that reducing the overall FA level by blocking FA biosynthesis or inhibiting protein myristoylation leads to disorganization of sarcomere structure and adult-onset paralysis. Further analysis indicates that myristoylation of two ARF guanosine triphosphatases (GTPases) critically mediates the effect of FA deficiency on sarcomere integrity through inducing endoplasmic reticulum (ER) stress and ER unfolded protein response (UPRER), which in turn leads to reduction of the level of sarcomere component PINCH and myosin disorganization. We thus present a mechanism that links FA signal, protein myristoylation, and ER homeostasis with muscle integrity, which provides valuable insights into the regulatory role of nutrients and ER homeostasis in muscle maintenance.

Keywords: ACS; ER stress; UNC-97/PINCH; acyl-CoA synthetase; arf-1.2; arf-3; eIF-2a; muscle degeneration; myristoylation; xbp-1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biosynthetic Pathways
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins / metabolism
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum Stress
  • Fatty Acids / metabolism*
  • Homeostasis*
  • Movement
  • Muscles / metabolism
  • Myosins / metabolism
  • Myristic Acid / metabolism*
  • Phosphorylation
  • Sarcomeres / metabolism*

Substances

  • Caenorhabditis elegans Proteins
  • Fatty Acids
  • Myristic Acid
  • Myosins