Inhibition of DNAJ-HSP70 interaction improves strength in muscular dystrophy
Rocio Bengoechea, … , Heather L. True, Conrad C. Weihl
Rocio Bengoechea, … , Heather L. True, Conrad C. Weihl
Published May 19, 2020
Citation Information: J Clin Invest. 2020;130(8):4470-4485. https://doi.org/10.1172/JCI136167.
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Research Article Cell biology Muscle biology

Inhibition of DNAJ-HSP70 interaction improves strength in muscular dystrophy

Abstract

Dominant mutations in the HSP70 cochaperone DNAJB6 cause a late-onset muscle disease termed limb-girdle muscular dystrophy type D1 (LGMDD1), which is characterized by protein aggregation and vacuolar myopathology. Disease mutations reside within the G/F domain of DNAJB6, but the molecular mechanisms underlying dysfunction are not well understood. Using yeast, cell culture, and mouse models of LGMDD1, we found that the toxicity associated with disease-associated DNAJB6 required its interaction with HSP70 and that abrogating this interaction genetically or with small molecules was protective. In skeletal muscle, DNAJB6 localizes to the Z-disc with HSP70. Whereas HSP70 normally diffused rapidly between the Z-disc and sarcoplasm, the rate of diffusion of HSP70 in LGMDD1 mouse muscle was diminished, probably because it had an unusual affinity for the Z-disc and mutant DNAJB6. Treating LGMDD1 mice with a small-molecule inhibitor of the DNAJ-HSP70 complex remobilized HSP70, improved strength, and corrected myopathology. These data support a model in which LGMDD1 mutations in DNAJB6 are a gain-of-function disease that is, counterintuitively, mediated via HSP70 binding. Thus, therapeutic approaches targeting HSP70-DNAJB6 may be effective in treating this inherited muscular dystrophy.

Authors

Rocio Bengoechea, Andrew R. Findlay, Ankan K. Bhadra, Hao Shao, Kevin C. Stein, Sara K. Pittman, Jil A.W. Daw, Jason E. Gestwicki, Heather L. True, Conrad C. Weihl

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Figure 8

JG231 increases myofiber size in LGMDD1 mice.

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JG231 increases myofiber size in LGMDD1 mice. (A) Representative mages o...
(A) Representative mages of TA, QUAD, and GAST muscles from 4-month-old DNAJB6b-WT and DNAJB6b-F93L mice treated with vehicle or JG231 for 4 weeks. (B) Average mass (mean ± SD, weight in milligrams) of the TA, QUAD, and GAST muscles from six DNAJB6b-WT and DNAJB6b-F93L mice treated with vehicle or JG231 for 4 or 8 weeks. **P < 0.005 and ***P < 0.0005, by paired Student’s t test. We used frozen sections of TA muscle from 4-month-old DNAJB6b-WT and DNAJB6b-F93L control mice or DNAJB6b-F93L mice treated with JG231 for 4 or 8 weeks. (C and D) Frequency distributions of muscle fiber CSA in TA muscle from 4-month-old DNAJB6b-F93L mice treated with vehicle or JG231 for 4 weeks (n = 6) (C) or 8 weeks (n = 4) (D). Data are presented as the average percentage of total fibers ± SD. *P < 0.05 and **P < 0.01, by 2-way ANOVA for comparisons between groups, followed by Bonferroni’s post hoc multiple comparisons test. ****P < 0.0001, by paired Student’s t test for comparisons between groups. Scatter plot graphs in C and D represent the mean CSA for all animals, where each point indicates an individual muscle fiber CSA.