title: The L-type Ca(2+) channel facilitates abnormal metabolic activity in the cTnI-G203S mouse model of hypertrophic cardiomyopathy.
abstract: 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.
  
  
  
  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 (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.
authors.affiliation: School of Anatomy, Physiology and Human Biology, The University of Western Australia, Crawley, WA, Australia.
authors.forename: Helena
authors.initials: H
authors.lastname: Viola
authors.affiliation: School of Anatomy, Physiology and Human Biology, The University of Western Australia, Crawley, WA, Australia.
authors.forename: Victoria
authors.initials: V
authors.lastname: Johnstone
authors.affiliation: School of Anatomy, Physiology and Human Biology, The University of Western Australia, Crawley, WA, Australia.
authors.forename: Henrietta
authors.initials: H
authors.lastname: Cserne Szappanos
authors.affiliation: The Harry Perkins Institute for Medical Research, The University of Western Australia, Crawley, WA, Australia.
authors.forename: Tara
authors.initials: T
authors.lastname: Richman
authors.affiliation: Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, NSW, Australia.|Sydney Medical School, University of Sydney, NSW, Australia.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Tsoutsman
authors.affiliation: The Harry Perkins Institute for Medical Research, The University of Western Australia, Crawley, WA, Australia.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Filipovska
authors.affiliation: Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, NSW, Australia.|Sydney Medical School, University of Sydney, NSW, Australia.|Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
authors.forename: Christopher
authors.initials: C
authors.lastname: Semsarian
authors.affiliation: School of Anatomy, Physiology and Human Biology, The University of Western Australia, Crawley, WA, Australia.|Victor Chang Cardiac Research Institute, Sydney, NSW, Australia.
authors.forename: Livia
authors.initials: L
authors.lastname: Hool
mesh_terms: D000199:Actins / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000502:physiology*; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics / Q000503:physiopathology*; D003599:Cytoskeleton / Q000502:physiology; D004110:Diltiazem / Q000494:pharmacology; D004195:Disease Models, Animal; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009154:Mutation; D032383:Myocytes, Cardiac / Q000502:physiology; D015737:Nisoldipine / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D019210:Troponin I / Q000235:genetics
chemical_list: D000199:Actins; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D019210:Troponin I; D013481:Superoxides; D015737:Nisoldipine; D004110:Diltiazem; D002118:Calcium