The L-type Ca²⁺ channel facilitates abnormal metabolic activity in the cTnI-G203S mouse model of hypertrophic cardiomyopathy

The Journal of Physiology © 2016 The Physiological SocietyKey points: Genetic mutations in cardiac troponin I (cTnI) are associated with development of hypertrophic cardiomyopathy characterized by myocyte remodelling, disorganization of cytoskeletal proteins and altered energy metabolism. The L-type Ca2+ channel is the main route for calcium influx and is crucial 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 the mitochondrial voltage-dependent anion channel, resulting in a ‘hypermetabolic’ mitochondrial state. We propose that L-type Ca2+ channel antagonists, such as diltiazem, might be effective in reducing the cardiomyopathy by normalizing mitochondrial metabolic activity. Abstract: Genetic mutations in cardiac troponin I (cTnI) account for 5% of families with hypertrophic cardiomyopathy. Hypertrophic cardiomyopathy is associated with disorganization 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 the channel and mitochondria via the cytoskeletal network. We investigate the role of ICa-L in regulating mitochondrial function in 25- to 30-week-old cardiomyopathic mice expressing the 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 vs. wild-type (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 vs. wt: 18.84 ± 2.01%, n = 10, P <0.05) and metabolic activity (24.40 ± 6.46%, n = 8 vs. wt: 9.98 ± 1.57%, n = 9, P <0.05). The responses occurred because of impaired communication between ICa-L and F-actin, involving lack of dynamic movement of actin–myosin and block of the mitochondrial voltage-dependent anion channel. Similar responses were observed in precardiomyopathic 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 might contribute to development of cTnI-G203S cardiomyopathy because the response is present in young precardiomyopathic mice. ICa-L antagonists might be effective in reducing the cardiomyopathy by altering mitochondrial function.