Viola 2016 J Physiol

Viola H, Johnstone V, Szappanos HC, Richman T, Tsoutsman T, Filipovska A, Semsarian C, Hool L (2016) The L-type Ca²⁺ channel facilitates abnormal metabolic activity in the cTnI-G203S mouse model of hypertrophic cardiomyopathy. J Physiol [Epub ahead of print].

» PMID: 27062056 Open Access

Viola H, Johnstone V, Szappanos HC, Richman T, Tsoutsman T, Filipovska A, Semsarian C, Hool L (2016) J Physiol

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 Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ 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.

Labels: MiParea: Respiration Pathology: Cardiovascular, Myopathy

Organism: Mouse Tissue;cell: Heart Preparation: Isolated mitochondria

HRR: Oxygraph-2k

Labels, 2016-06