- 作者: Po-Jui Hsu, Horng-Dar Wang, Yung-Che Tseng, Shao-Wei Pan, Bonifasius Putera Sampurna, Yuh-Jyh Jong and Chiou-Hwa Yuh
- 作者服務機構: 1. Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan 2. Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan 3. Department of Laboratory Medicine, Mackay Memorial Hospital, Taipei, Taiwan 4. Marine Research Station, Institute of Cellular and Organismic Biology, Academia Sinica, I-Lan County, Taiwan 5. Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan 6.Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 7. Departments of Pediatrics and Laboratory Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 8. Translational Research Center of Neuromuscular Diseases, Kaohsiung Medical University, Kaohsiung, Taiwan 9. Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan 10. Ph.D. Program in Environmental and Occupational Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- 中文摘要:
- 英文摘要:
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. - 中文關鍵字:
- 英文關鍵字: Congenital myopathy, Zebrafsh, Tropomyosin 3 (TPM3), l-Carnitine