Viola, Helena and Johnstone, Vicky and Szappanos, Henrietta Cserne and Richman, Tara and Tsoutsman, Tatiana and Filipovska, Aleksandra and Semsarian, Christopher and Hool, Livia (2016) The L-type Ca(2+) channel facilitates abnormal metabolic activity in the cTnI-G203S mouse model of hypertrophic cardiomyopathy. The Journal of Physiology, 594 (14). pp.4051-4070. ISSN 1469-7793 (PMC OA)
Full text not available from this repository.Abstract
KEY POINTS
Genetic mutations in cardiac troponin I (cTnI) are associated with development of hypertrophic cardiomyopathy characterised by myocyte remodeling, disorganisation of cytoskeletal proteins and altered energy metabolism. The L-type Ca(2+) channel is the main route for calcium influx and critical to cardiac excitation and contraction. The channel also regulates mitochondrial function in the heart by a functional communication between the channel and mitochondria via the cytoskeletal network. We find that L-type Ca(2+) channel kinetics are altered in cTnI-G203S cardiac myocytes, and that activation of the channel causes a significantly greater increase in mitochondrial membrane potential and metabolic activity in cTnI-G203S cardiac myocytes. These responses occur as a result of impaired communication between the L-type Ca(2+) channel and cytoskeletal protein F-actin, involving decreased movement of actin-myosin, and block of mitochondrial VDAC, resulting in a 'hypermetabolic' mitochondrial state. We propose that L-type Ca(2+) channel antagonists such as diltiazem may be effective in reducing the cardiomyopathy by normalising mitochondrial metabolic activity.
ABSTRACT
Genetic mutations in cardiac troponin I (cTnI) account for 5% of families with hypertrophic cardiomyopathy (HCM). HCM is associated with disorganisation of cytoskeletal proteins and altered energy metabolism. The L-type Ca(2+) channel (ICa-L ) plays an important role in regulating mitochondrial function. This involves a functional communication between ICa-L and mitochondria via the cytoskeletal network. We investigate the role of ICa-L in regulating mitochondrial function in 25-30-week old cardiomyopathic mice expressing human disease causing mutation Gly203Ser in cTnI (cTnI-G203S). The inactivation rate of ICa-L is significantly faster in cTnI-G203S myocytes (cTnI-G203S: τ1 = 40.68 ± 3.22, n = 10 versus wt: τ1 = 59.05 ± 6.40, n = 6, P < 0.05). Activation of ICa-L caused a greater increase in mitochondrial membrane potential (Ψm , 29.19 ± 1.85%, n = 15 versus wt: 18.84 ± 2.01%, n = 10, P < 0.05) and metabolic activity (24.40 ± 6.46%, n = 8 versus wt: 9.98 ± 1.57%, n = 9, P < 0.05). The responses occurred due to impaired communication between ICa-L and F-actin, involving lack of dynamic movement of actin-myosin, and block of mitochondrial VDAC. Similar responses were observed in pre-cardiomyopathic mice. ICa-L antagonists nisoldipine and diltiazem decreased Ψm to basal levels. We conclude that the Gly203Ser mutation leads to impaired functional communication between ICa-L and mitochondria resulting in a 'hypermetabolic' state. This may contribute to development of cTnI-G203S cardiomyopathy because the response is present in young pre-cardiomyopathic mice. ICa-L antagonists may be effective in reducing the cardiomyopathy by altering mitochondrial function. This article is protected by copyright. All rights reserved.
| Item Type: | Article |
|---|---|
| Additional Information: | This article is available for free from the PMC website. |
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 17 Jun 2016 05:10 |
| Last Modified: | 30 Aug 2017 06:03 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/457 |
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