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.
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Research Article Muscle biology Therapeutics Article has an altmetric score of 12

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

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

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Figure 5

DNM2 reduction rescues skeletal muscle histology and improves contractility in extensor digitorum longus muscles of Speg-rescue mice.

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DNM2 reduction rescues skeletal muscle histology and improves contractil...
(A) Representative TA muscle images of control, Speg-KO, and Speg-rescue mice at 3 months of age. (B) H&E stains of TA muscles from control, Speg-KO, and Speg-rescue mice at 3 months of age. Scale bar: 100 μm. (C) Distribution of the cross-sectional area (CSA) in control, Speg-KO, and Speg-rescue TA muscles (n = 4 per group). (D) The mean CSA of Speg-rescue TA muscles is significantly larger than that of Speg-KO (****P < 0.0001, over 500 fibers were analyzed from each group; 1-way ANOVA with Tukey’s post hoc test). (E) Absolute peak tetanic force was significantly reduced in EDL muscles from Speg-KO mice compared with muscles from control animals. Muscles from the Speg-rescue mice were not different from either of the other groups. (F) Peak tetanic force expressed relative to EDL physiological CSA. Peak force/CSA was significantly reduced in Speg-KO animals (compared with control) but was restored to control levels in the Speg-rescue group. (G) Force-frequency relationships of EDL muscles. Forces obtained at different frequencies of stimulation were expressed relative to peak force and fit by the equation Pmin + ([Pmax – Pmin]/[1+([K/Hz]H)]), where Pmin is the minimum force, Pmax is the maximum force, K is the frequency corresponding to the inflection point of the curve, and H is a unitless parameter defining the curve’s slope. (H) The parameter K was significantly greater for the Speg-KO and the Speg-rescue EDL muscles compared with control, indicating a significant shift of the Speg-KO curve to the right. The parameter H did not differ between control (4.05 ± 0.21), Speg-KO (3.74 ± 0.04), and Speg-rescue (4.32 ± 0.22) muscles. *P ˂ 0.05; **P ˂ 0.01; ***P ˂ 0.001, n = 5 per genotype; 1-way ANOVA with Tukey’s post hoc test.