Muscle death participates in myofibrillar abnormalities in FHL1 knockout mice

Biochem Biophys Res Commun. 2020 Feb 26;523(1):105-111. doi: 10.1016/j.bbrc.2019.12.026. Epub 2019 Dec 10.

Abstract

Background: Mutations in the four and-a-half LIM domain protein 1 (FHL1) gene or FHL1 protein deletion have been identified as the cause of rare hereditary myopathies or cardiomyopathies. In our previous study, autophagy activation was associated with myofibrillar abnormalities in FHL1 knockout (KO) mice. P2RX7 induces cell death, such as autophagy, pyroptosis or apoptosis via cell-specific downstream signaling; however, the roles of P2RX7 in pyroptosis or apoptosis in myofibrillar abnormalities in FHL1 KO mice have not been well elucidated.

Methods: In this study, skeletal muscle and heart of 2.5 months old WT and FHL1 KO male mice histomorphology were examined by hematoxylin and eosin staining. The indicators for pyroptosis (NLRP3; ASC; cleaved-caspase1; IL-1β), apoptosis (Apaf-1; Bcl-2; caspase9; cleaved-caspase3), and P2RX7 were detected in the triceps (Tri), tibialis anterior muscles (TA), and heart by western blot and/or immunohistochemistry in WT and FHL1 KO male mice.

Results: Indicators for pyroptosis (ASC; cleaved-caspase1; IL-1β) and apoptosis (Apaf-1 and cleaved-caspase3), as well as P2RX7 were upregulated in Tri, tibialis TA, and heart in FHL1 KO mice, indicating pyroptosis and apoptosis play important roles in myofibrillar abnormalities in FHL1 KO mice.

Conclusions: P2RX7 may participate in myofibrillar abnormalities by activating pyroptosis and apoptosis in FHL1 KO mice. These findings have basic implications for the understanding of myopathies induced by FHL1 deficiency and provide new avenues for the treatment of these hereditary myopathies by modulating P2RX7.

Keywords: FHL1; Myopathy; P2RX7; Pyroptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Intracellular Signaling Peptides and Proteins / deficiency*
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • LIM Domain Proteins / deficiency*
  • LIM Domain Proteins / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Muscle Proteins / deficiency*
  • Muscle Proteins / metabolism*
  • Muscle, Skeletal / metabolism
  • Muscular Diseases / metabolism*
  • Muscular Diseases / pathology
  • Receptors, Purinergic P2X7 / metabolism

Substances

  • Fhl1 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • LIM Domain Proteins
  • Muscle Proteins
  • P2rx7 protein, mouse
  • Receptors, Purinergic P2X7