Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
Dynamin-2 reduction rescues the skeletal myopathy of a SPEG-deficient mouse model
Qifei Li, … , Xiaoli Liu, Pankaj B. Agrawal
Qifei Li, … , Xiaoli Liu, Pankaj B. Agrawal
Published June 28, 2022
Citation Information: JCI Insight. 2022;7(15):e157336. https://doi.org/10.1172/jci.insight.157336.
View: Text | PDF
Research Article Muscle biology Therapeutics

Dynamin-2 reduction rescues the skeletal myopathy of a SPEG-deficient mouse model

  • Text
  • PDF
Abstract

Striated preferentially expressed protein kinase (SPEG), a myosin light chain kinase, is mutated in centronuclear myopathy (CNM) and/or dilated cardiomyopathy. No precise therapies are available for this disorder, and gene replacement therapy is not a feasible option due to the large size of SPEG. We evaluated the potential of dynamin-2 (DNM2) reduction as a potential therapeutic strategy because it has been shown to revert muscle phenotypes in mouse models of CNM caused by MTM1, DNM2, and BIN1 mutations. We determined that SPEG-β interacted with DNM2, and SPEG deficiency caused an increase in DNM2 levels. The DNM2 reduction strategy in Speg-KO mice was associated with an increase in life span, body weight, and motor performance. Additionally, it normalized the distribution of triadic proteins, triad ultrastructure, and triad number and restored phosphatidylinositol-3-phosphate levels in SPEG-deficient skeletal muscles. Although DNM2 reduction rescued the myopathy phenotype, it did not improve cardiac dysfunction, indicating a differential tissue-specific function. Combining DNM2 reduction with other strategies may be needed to target both the cardiac and skeletal defects associated with SPEG deficiency. DNM2 reduction should be explored as a therapeutic strategy against other genetic myopathies (and dystrophies) associated with a high level of DNM2.

Authors

Qifei Li, Jasmine Lin, Jeffrey J. Widrick, Shiyu Luo, Gu Li, Yuanfan Zhang, Jocelyn Laporte, Mark A. Perrella, Xiaoli Liu, Pankaj B. Agrawal

×

Figure 3

DNM2 reduction increases the life span and whole-body weight in Speg-rescue mice.

Options: View larger image (or click on image) Download as PowerPoint
DNM2 reduction increases the life span and whole-body weight in Speg-res...
(A) Life span of all Speg-rescue, Speg-KO, and control mice was monitored until 48 weeks of age. Data were represented as percentage survival (control, n = 35; Speg-KO, n = 26; Speg-rescue, n = 35). Survival rate for male (B) and female mice (C) were shown separately (for males: control, n = 21; Speg-KO, n = 12; Speg-rescue, n = 21; for females: control, n = 14; Speg-KO, n = 14; Speg-rescue, n = 14). Body weight of male (D) and female mice (E) was measured at different time points once per week and monitored until 32 weeks (for males: control, n = 14; Speg-KO, n = 6; Speg-rescue, n = 15; for females: control, n = 12; Speg-KO, n = 9; Speg-rescue, n = 10). The average body weight of male Speg-rescue mice begins to differentiate from that of Speg-KO mice at 13 weeks of age (*P ˂ 0.05; 1-way ANOVA with Tukey’s post hoc test) and remains higher afterward, while the average body weight of female Speg-KO and Speg-rescue mice is not significantly different at most of the time points.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts