Coupling calcium binding to troponin C and cross-bridge cycling in skinned cardiac cells

Landesberg, Amir; Sideman, S.

doi:10.1152/ajpheart.1994.266.3.h1260

Cited by 74 publications

(126 citation statements)

References 12 publications

Supporting

Mentioning

118

Contrasting

Order By: Relevance

“…k off(TnC⅐Ca) therefore becomes smaller as cross-bridges form and force develops (34,37,38). The exponential dependence of k off(TnC⅐Ca) on force is based on experimental observations in cardiac and skeletal muscle (32)(33)(34) and is quantified by the equation k off.TnC⅐Ca ϭ k off.TnC⅐Ca.rest ϫ e Ϫgain ϫ relative force , where k off.TnC⅐Ca.rest is the off-rate of Ca 2ϩ from TnC in the absence of force development. For the simulations used in this study, gain was set at 8.…”

Section: Force Dependence Of Affinity Of Tnc For Ca 2ϩmentioning

confidence: 99%

Functional Analysis of a Troponin I (R145G) Mutation Associated with Familial Hypertrophic Cardiomyopathy

Lang¹,

Gomes²,

Zhao³

et al. 2002

Journal of Biological Chemistry

View full text Add to dashboard Cite

Familial hypertrophic cardiomyopathy has been associated with several mutations in the gene encoding human cardiac troponin I (HCTnI). A missense mutation in the inhibitory region of TnI replaces an arginine residue at position 145 with a glycine and cosegregates with the disease. Results from several assays indicate that the inhibitory function of HCTnI R145G is significantly reduced. When HCTnI R145G was incorporated into whole troponin, Tn R145G (HCTnT⅐HCTnI R145G ⅐HCTnC), only partial inhibition of the actin-tropomyosin-myosin ATPase activity was observed in the absence of Ca 2؉ compared with wild type Tn (HCTnT⅐HCTnI⅐HCTnC). Maximal activation of actin-tropomyosin-myosin ATPase in the presence of Ca 2؉ was also decreased in Tn R145G when compared with Tn. Using skinned cardiac muscle fibers, we determined that in comparison with the wild type complex 1) the complex containing HCTnI R145G only inhibited 84% of Ca 2؉ -unregulated force, 2) the recovery of Ca 2؉ -activated force was decreased, and 3) there was a significant increase in the Ca 2؉ sensitivity of force development. Computer modeling of troponin C and I variables predicts that the primary defect in TnI caused by these mutations would lead to diastolic dysfunction. These results suggest that severe diastolic dysfunction and somewhat decreased contractility would be prominent clinical features and that hypertrophy could arise as a compensatory mechanism. Familial hypertrophic cardiomyopathy (FHC)1 has been linked to mutations in genes of nine different sarcomeric proteins. These mutations have been found in the genes for ␣-myosin heavy chain (1), cardiac myosin essential light chain and cardiac myosin regulatory light chain (2), ␣-tropomyosin, cardiac troponin T (TnT) (3), cardiac myosin-binding protein C (4, 5), troponin I (TnI) (6), ␣-actin (7), as well as titin (8), and possibly troponin C (TnC) (9). This disease has recently gained significant attention due to several highly publicized reports of sudden death and fainting spells in young athletes who were asymptomatic and otherwise healthy individuals. In general, patients with FHC demonstrate an increase in heart muscle mass and sometimes an irregular echocardiogram (10). Kimura et al. (6) reported five missense mutations in TnI, R145G, R145Q, R162W, G203S, and K206Q, that cosegregate with FHC (Fig. 1). Three other TnI FHC mutants (S199N, Lys-183 deletion, and an exon 8 deletion mutant encompassing the stop codon of the cardiac TnI gene) have recently been discovered (11, 12). Functionally TnI is the inhibitory subunit of the troponin (Tn) complex that controls the interaction between actin and myosin in a Ca 2ϩ -dependent manner (13-15). Studies using proteolytic fragments of fast skeletal TnI identified the central TnI sequence (residues 96 -116) as being responsible for its inhibitory activity. Residues 104 -115 of fast skeletal TnI (comparable to residues 136 -147 in cardiac TnI) formed the minimum sequence necessary for inhibition of muscle contraction (16 -19). Two of these mutations occ...

show abstract

Section: Force Dependence Of Affinity Of Tnc For Ca 2ϩmentioning

confidence: 99%

Functional Analysis of a Troponin I (R145G) Mutation Associated with Familial Hypertrophic Cardiomyopathy

Lang¹,

Gomes²,

Zhao³

et al. 2002

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Computer -specific site II) on force (51,52). A detailed description of the model is provided in the "Appendix.…”

Section: Simultaneous Force and Atpase Measurements In Fresh (Not Glymentioning

confidence: 99%

“…k off(TnC⅐Ca) therefore becomes smaller as crossbridges form and force develops (47,51,69). The off rate of Ca 2ϩ from TnC was made to depend on force as follows.…”

Section: Mathematical Model Of Intracellular Ca 2ϩ Handling and Forcementioning

confidence: 99%

Abnormal Contractile Function in Transgenic Mice Expressing a Familial Hypertrophic Cardiomyopathy-linked Troponin T (I79N) Mutation

Miller

Szczêsna

Housmans

et al. 2001

Journal of Biological Chemistry

113

106

View full text Add to dashboard Cite

This study characterizes a transgenic animal model for the troponin T (TnT) mutation (I79N) associated with familial hypertrophic cardiomyopathy. To study the functional consequences of this mutation, we examined a wild type and two I79N-transgenic mouse lines of human cardiac TnT driven by a murine ␣-myosin heavy chain promoter. Extensive characterization of the transgenic I79N lines compared with wild type and/or nontransgenic mice demonstrated: 1) normal survival and no cardiac hypertrophy even with chronic exercise; 2) large increases in Ca 2؉ sensitivity of ATPase activity and force in skinned fibers; 3) a substantial increase in the rate of force activation and an increase in the rate of force relaxation; 4) lower maximal force/cross-sectional area and ATPase activity; 5) loss of sensitivity to pHinduced shifts in the Ca 2؉ dependence of force; and 6) computer simulations that reproduced experimental observations and suggested that the I79N mutation decreases the apparent off rate of Ca 2؉ from troponin C and increases cross-bridge detachment rate g. Simulations for intact living fibers predict a higher basal contractility, a faster rate of force development, slower relaxation, and increased resting tension in transgenic I79N myocardium compared with transgenic wild type. These mechanisms may contribute to mortality in humans, especially in stimulated contractile states.

show abstract

“…The early isotonic shortening induces "shortening deactivation", or what Brutsaert and colleagues (23-25) thought of as "load-dependent relaxation". This has been explored by David Allen (1,2) and pulled together in a quantitative comprehensive theoretical study by Landesberg and Sideman (58,59). Rapid shortening against low resistance causes reduction in the amount of calcium bound to myosin ATPase in the "strong" form, and reduces ATP hydrolysis.…”

Section: Shown Inmentioning

confidence: 99%

The mechanical and metabolic basis of myocardial blood flow heterogeneity

Bassingthwaighte

Beard

2001

Basic Research in Cardiology

View full text Add to dashboard Cite

Precise measurements of regional myocardial blood flow heterogeneity had to be developed before one could seek causation for the heterogeneity. Deposition techniques (particles or molecular microspheres) are the most precise, but imaging techniques have begun to provide high enough resolution to allow in vivo studies. Assigning causation has been difficult. There is no apparent association with the regional concentrations of energy-related enzymes or substrates, but these are measures of status, not of metabolism. There is statistical correlation between flow and regional substrate uptake and utilization. Attribution of regional flow variation to vascular anatomy or to vasomotor control appears not to be causative on a long-term basis. The closest relationships appear to be with mechanical function, but one cannot say for sure whether this is related to ATP hydrolysis at the crossbridge or associated metabolic reactions such as calcium uptake by the sarcoplasmic reticulum.

show abstract

Coupling calcium binding to troponin C and cross-bridge cycling in skinned cardiac cells

Cited by 74 publications

References 12 publications

Functional Analysis of a Troponin I (R145G) Mutation Associated with Familial Hypertrophic Cardiomyopathy

Functional Analysis of a Troponin I (R145G) Mutation Associated with Familial Hypertrophic Cardiomyopathy

Abnormal Contractile Function in Transgenic Mice Expressing a Familial Hypertrophic Cardiomyopathy-linked Troponin T (I79N) Mutation

The mechanical and metabolic basis of myocardial blood flow heterogeneity

Contact Info

Product

Resources

About