PUBLICATION
L-Carnitine ameliorates congenital myopathy in a tropomyosin 3 de novo mutation transgenic zebrafish
- Authors
- Hsu, P.J., Wang, H.D., Tseng, Y.C., Pan, S.W., Sampurna, B.P., Jong, Y.J., Yuh, C.H.
- ID
- ZDB-PUB-210114-8
- Date
- 2021
- Source
- Journal of Biomedical Science 28: 8 (Journal)
- Registered Authors
- Tseng, Yung-Che, Yuh, Chiou-Hwa (Cathy)
- Keywords
- Congenital myopathy, L-Carnitine, Tropomyosin 3 (TPM3), Zebrafish
- Datasets
- GEO:GSE149261
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Carnitine/metabolism*
- Muscle, Skeletal/metabolism
- Myotonia Congenita/metabolism*
- Tropomyosin/chemistry
- Tropomyosin/genetics*
- Tropomyosin/metabolism
- Zebrafish/abnormalities
- Zebrafish/metabolism
- PubMed
- 33435938 Full text @ J. Biomed. Sci.
Citation
Hsu, P.J., Wang, H.D., Tseng, Y.C., Pan, S.W., Sampurna, B.P., Jong, Y.J., Yuh, C.H. (2021) L-Carnitine ameliorates congenital myopathy in a tropomyosin 3 de novo mutation transgenic zebrafish. Journal of Biomedical Science. 28:8.
Abstract
Background Congenital myopathy (CM) is a group of clinically and genetically heterogeneous muscle disorders, characterized by muscle weakness and hypotonia from birth. Currently, no definite treatment exists for CM. A de novo mutation in Tropomyosin 3-TPM3(E151G) was identified from a boy diagnosed with CM, previously TPM3(E151A) was reported to cause CM. However, the role of TPM3(E151G) in CM is unknown.
Methods Histopathological, swimming behavior, and muscle endurance were monitored in TPM3 wild-type and mutant transgenic fish, modelling CM. Gene expression profiling of muscle of the transgenic fish were studied through RNAseq, and mitochondria respiration was investigated.
Results While TPM3(WT) and TPM3(E151A) fish show normal appearance, amazingly a few TPM3(E151G) fish display either no tail, a crooked body in both F0 and F1 adults. Using histochemical staining for the muscle biopsy, we found TPM3(E151G) displays congenital fiber type disproportion and TPM3(E151A) resembles nemaline myopathy. TPM3(E151G) transgenic fish dramatically swimming slower than those in TPM3(WT) and TPM3(E151A) fish measured by DanioVision and T-maze, and exhibit weaker muscle endurance by swimming tunnel instrument. Interestingly, L-carnitine treatment on TPM3(E151G) transgenic larvae significantly improves the muscle endurance by restoring the basal respiration and ATP levels in mitochondria. With RNAseq transcriptomic analysis of the expression profiling from the muscle specimens, it surprisingly discloses large downregulation of genes involved in pathways of sodium, potassium, and calcium channels, which can be rescued by L-carnitine treatment, fatty acid metabolism was differentially dysregulated in TPM3(E151G) fish and rescued by L-carnitine treatment.
Conclusions These results demonstrate that TPM3(E151G) and TPM3(E151A) exhibit different pathogenicity, also have distinct gene regulatory profiles but the ion channels were downregulated in both mutants, and provides a potential mechanism of action of TPM3 pathophysiology. Our results shed a new light in the future development of potential treatment for TPM3-related CM.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping