The L‐type Ca 2+ channel facilitates abnormal metabolic activity in the cTnI‐G203S mouse model of hypertrophic cardiomyopathy

Key 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 Ca 2+ 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 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 the mitochondrial voltage‐dependent anion channel, resulting in a ‘hypermetabolic’ mitochondrial state. We propose that L‐type Ca 2+ 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 Ca 2+ channel (I Ca‐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 I Ca‐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 I Ca‐L is significantly faster in cTnI‐G203S myocytes [ cTnI‐G203S : τ 1  = 40.68 ± 3.22, n  = 10 vs . wild‐type ( wt ): τ 1  = 59.05 ± 6.40, n  = 6, P  < 0.05]. Activation of I Ca‐L caused a greater increase in mitochondrial membrane potential (Ψ m , 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 I Ca‐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. I Ca‐L antagonists nisoldipine and diltiazem decreased Ψ m to basal levels. We conclude that the Gly203Ser mutation leads to impaired functional communication between I Ca‐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. I Ca‐L antagonists might be effective in reducing the cardiomyopathy by altering mitochondrial function.