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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

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

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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 7

Restoration of PI3P levels in the Speg-rescue mice.

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Restoration of PI3P levels in the Speg-rescue mice.
(A) Immunoblot and q...
(A) Immunoblot and quantification of MTM1 expression in triceps (****P ˂ 0.0001, n = 3 per genotype; 1-way ANOVA with Tukey’s post hoc test). (B) PI3P levels are increased in Speg-KO muscle, while PI3P levels in Speg-rescue muscle are similar to control muscle, as determined using a PI3P ELISA kit [purified lipid (pmol)/mass (g) of quadriceps muscle]. PI3P levels in control muscle = 71.5 ± 15.1 pmol/g (n = 4), Speg-KO muscle = 166.5 ± 6.5 pmol/g (n = 4), and Speg-rescue muscle = 78.1 ± 10.8 pmol/g (n = 3). ****P < 0.0001; 1-way ANOVA with Tukey’s post hoc test. (C) Immunostaining for PI3P on TA muscle. Abnormal PI3P accumulation (denoted by arrows) was detected in discrete areas of Speg-KO myofibers yet absent in Speg-rescue mice. Scale bar: 50 μm; over 100 fibers were analyzed from each group, n ≥ 3 per genotype.

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ISSN 2379-3708

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