Reduced expression of MYBPC3 causes early dysfunction in human cell culture models prior to reduced cMyBP-C levels.
Similar to HCM-causing truncation mutations, CRISPR-mediated cMyBP-C ablation in iPSC-derived human engineered cardiac tissue constructs causes cMyBP-C haploinsufficiency in the heterozygous state. While cMyBP-C ablation causes early hypercontractility, developing Ca2+-handling abnormalities leads to progressive contractile dysfunction.
In olfactory transduction, Ca2+ signaling is used for two opposing functions, namely signal boosting and signal reduction through adaptation, which could be interpreted to compensate for each other. Here, however, we show that these functions are clearly segregated by molecular dynamics.
N-terminal truncated cardiac troponin I enhances Frank-Starling response by increasing myofilament sensitivity to resting tension
This article reports that restrictive deletion of the N-terminal extension of cardiac troponin I as seen in adaptation to heart failure enhances Frank-Starling response of the heart by increasing myofilament sensitivity to passive tension rather than resting sarcomere length.
Myosin-binding protein C stabilizes, but is not the sole determinant of SRX myosin in cardiac muscle
Striated muscle functional regulation occurs through the sequestration of myosin into the super-relaxed (SRX) state. Observing the turnover of single ATP molecules within cardiac sarcomeres defines the spatial arrangement of SRX myosin and their regulation by myosin-binding protein C.
Infield and co-authors introduce an approach whereby the individual functional contribution of phosphoserine residues can be observed in real time via site-specific encoding of a caged-serine unnatural amino acid.
Screening for bilayer-active and likely cytotoxic molecules reveals bilayer-mediated regulation of cell function
Drug-induced changes in bilayer properties alter the function of diverse membrane proteins, thereby changing cell function, which may cause cytotoxicity. Drug-induced changes in bilayer properties can be quantified as shifts in the gramicidin monomer↔dimer equilibrium, which allows for quantifying the likelihood a drug is cytotoxic.
In the human CFTR anion channel, an hR117-hE1124 H-bond stabilizes the bursting state, and the hR117H mutation causes cystic fibrosis. Instead, in zebrafish CFTR, a zS109-zN120 H-bond stabilizes bursts through an alternative mechanism. Although serine and arginine are conserved, their interactions have evolved to increase the open probability in hCFTR.
The effect of RLC phosphorylation on Ca2+ sensitivity of contraction is amplified when cMyBP-C is absent from the sarcomere. These data indicate that cMyBP-C and RLC may act in concert to regulate contractility in healthy and diseased cardiac muscles.
Probenecid affects muscle Ca2+ homeostasis and contraction independently from pannexin channel block
Probenecid, an FDA-approved gout medication of therapeutic interest for other disease conditions, depresses sarcoplasmic reticulum Ca2+ release and contractile activation in mouse skeletal muscle. The effects are unrelated to its capacity to block ATP release through pannexin-1 channels.
Cardiomyocyte sarcomere length variability: Membrane fluorescence versus second harmonic generation myosin imaging
Cardiomyocyte sarcomere length (SL) variability assessed by second-harmonic generation (SHG) was significantly less than that by ANEPPS confocal fluorescence. We conclude that SHG-derived SL variability may reflect the true relaxed myocyte sarcomeric ultrastructure.