Search

Based on the framework of sliding-filament theory and on the cross-bridges dynamics, a mathematical model for the simulation of the force response and length change of individual myofibril is presented. The myofibril is modeled as a group of segments placed in series, each segment represents a half-sarcomere with active and elastic properties. A multiple-state cross-bridge formalism relates the half Sarcomere force to the chemical kinetics of ATP hydrolysis. The corresponding system of nonlinear nonlocal partial differential equations of the model is analyzed. A numerical approach is introduced and some numerical tests are performed. The proposed in-silico model enables the study of biologically relevant process in the muscle contraction process, also in the case of muscular diseases, with reasonable computational effort.

Many genetic mutations in sarcomeric proteins, including the cardiac myosin regulatory light chain (RLC) encoded by the MYL2 gene, have been implicated in familial cardiomyopathies. Yet, the molecular mechanisms by which these mutant proteins regulate cardiac muscle mechanics in health and disease remain poorly understood. Evidence has been accumulating that RLC phosphorylation has an influential role in striated muscle contraction and, in addition to the conventional modulation via Ca2+ binding to troponin C, it can regulate cardiac muscle function. In this review, we focus on RLC mutations that have been reported to cause cardiomyopathy phenotypes via compromised RLC phosphorylation and elaborate on pseudo-phosphorylation rescue mechanisms. This new methodology has been discussed as an emerging exploratory tool to understand the role of phosphorylation as well as a genetic modality to prevent/rescue cardiomyopathy phenotypes. Finally, we summarize structural effects post-phosphorylation, a phenomenon that leads to an ordered shift in the myosin S1 and RLC conformational equilibrium between two distinct states.

To determine whether a capsaicin-sensitive local neural circuit constitutively modulates vagal neuromuscular transmission in the esophageal striated muscle or whether the neural circuit operates in a stimulus-dependent manner, we compared the motility of esophageal preparations isolated from intact rats with those in which capsaicin-sensitive neurons had been destroyed. Electrical stimulation of the vagus nerve trunk evoked contractile responses in the esophagus isolated from a capsaicin-treated rat in a manner similar to those in the esophagus from a control rat. No obvious differences were observed in the inhibitory effects of D-tubocurarine on intact and capsaicin-treated rat esophageal motility. Destruction of the capsaicin-sensitive neurons did not significantly affect latency, time to peak and duration of a vagally evoked twitch-like contraction. These findings indicate that the capsaicin-sensitive neural circuit does not operate constitutively but rather is activated in response to an applied stimulus.

The regulation of striated muscle contraction involves cooperative interactions between actin filaments, myosin-S1 (S1), tropomyosin (Tm), troponin (Tn), and calcium. These interactions are modeled by treating overlapping tropomyosins as a continuous flexible chain (CFC), weakly confined by electrostatic interactions with actin. The CFC is displaced locally in opposite directions on the actin surface by the binding of either S1 or Troponin I (TnI) to actin. The apparent rate constants for myosin and TnI binding to and detachment from actin are then intrinsically coupled via the CFC model to the presence of neighboring bound S1s and TnIs. Monte Carlo simulations at prescribed values of the CFC stiffness, the CFC’s degree of azimuthal confinement, and the angular displacements caused by the bound proteins were able to predict the stopped-flow transients of S1 binding to regulated F-actin. The transients collected over a large range of calcium concentrations could be well described by adjusting a single calcium-dependent parameter, the rate constant of TnI detachment from actin, k−I. The resulting equilibrium constant \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ K_{\text{B}} \equiv 1/K_{\text{I}} $$\end{document} varied sigmoidally with the free calcium, increasing from 0.12 at low calcium (pCa >7) to 12 at high calcium (pCa

Striated muscle contraction is regulated primarily through the action of tropomyosin and troponin that are bound to actin. Activation requires Ca(2+) binding to troponin and/or binding of high affinity myosin complexes to actin. Mutations within components of the regulatory complex may lead to familial cardiomyopathies and myopathies. In several cases examined, either physiological or pathological changes in troponin alter the distribution among states of actin-tropomyosin-troponin that differ in their abilities to stimulate myosin ATPase activity. These observations open possibilities for managing disorders of the troponin complex. Furthermore, analyses of mutant forms of troponin give insights into the regulation of striated muscle contraction.

Several striated muscle myopathies have been directly linked to mutations in contractile and associated proteins. Troponin T (TnT) is one of the three subunits that form troponin (Tn) which together with tropomyosin is responsible for the regulation of striated muscle contraction. All three subunits of cardiac Tn as well as tropomyosin have been associated with hypertrophic cardiomyopathy (HCM). However, TnT accounts for most of the mutations that cause HCM in these regulatory proteins. To date 30 mutations have been identified in the cardiac TnT (CTnT) gene that results in familial HCM (FHC). The CTnT gene has also been associated with familial dilated cardiomyopathy (DCM). CTnT deficiency is lethal due to impaired cardiac development. A recessive nonsense mutation in the gene encoding slow skeletal TnT has been associated with an unusual, severe form of nemaline myopathy among the Old Order Amish. How each mutation leads to the diverse clinical symptoms associated with FHC, DCM or nemaline myopathy is unclear. However, the use of animal model systems, in particular transgenic mice, has significantly increased our knowledge of normal and myopathic muscle physiology. In this review, we focus on the role of TnT in muscle physiology and disease.

Although there are studies showing that the amplitude of contraction in the distal esophageal body may be lower in gastroesophageal reflux (GER) disease than in asymptomatic subjects, there are no data about proximal striated muscle contraction in this disease. We studied the esophageal contraction 2 or 3 cm below the upper esophageal sphincter in response to swallowing a 5-ml bolus of water in 122 consecutive patients submitted to esophageal manometry who complained of heartburn and acid regurgitation. Sixty-nine had esophagitis seen at endoscopy. Thirty-three also complained of dysphagia. No patients had esophageal stenosis, esophageal motility abnormalities in distal esophagus, chest pain, or extraesophageal manifestations of GER. We also studied 20 patients with systemic sclerosis (SSc), a disease with no involvement of striated muscle. When we measured the amplitude, duration, and area under the curve (AUC) of the proximal esophageal contraction, we did not find any differences (P > 0.05) between patients with esophagitis (N = 69) or without esophagitis (N = 53), with dysphagia (N = 33) or without dysphagia (N = 89), with mild (N = 55) or severe (N = 14) esophagitis, or younger than 40 years (N = 45) or older than 60 years (N = 19). There was also no difference between patients with GER symptoms and patients with SSc (P > 0.05). We conclude that patients with GER symptoms with or without esophagitis and with or without dysphagia have similar esophageal striated muscle contractions.

Many studies have been conducted analyzing the manometric properties of patients with achalasia, but the striated portion of the esophagus has never been analyzed and is often overlooked. We retrospectively reviewed 120 manometric tracings (20 achalasia, 100 controls) performed between 1994 and 1997 and excluded tracings from patients with chronic cough and nutcracker esophagus. The data were assessed for age, sex, symptoms, duration of symptoms, lower esophageal sphincter pressure, gastroesophageal gradient, upper esophageal sphincter pressure, smooth muscle contraction amplitude and duration, striated muscle contraction amplitude and duration, length from upper esophageal sphincter to maximal striated muscle contraction, and esophageal length. The maximum striated muscle contraction amplitude was significantly decreased in achalasia patients with a median amplitude of 45 mm Hg (range 12-95) vs 76 mm Hg (range 30-210) in the control group (P = 0.002). Although the wave forms were similar, the maximum striated muscle contraction duration and the distance from the upper esophageal sphincter in achalasia patients was not significantly different from controls. The length of the esophagus was significantly longer in achalasia patients with a median value of 25 cm (range 21-30) vs 21 cm (range 17-26) in the control group (P < 0.001). Patients with achalasia have significantly lower maximum striated muscle contraction amplitudes and longer esophagi, but the duration of the contractions and the configuration of the wave forms are not different.

Troponin T (TnT) is present in striated muscle of vertebrates and invertebrates as a group of homologous proteins with molecular weights usually in the 31–36kDa range. It occupies a unique role in the regulatory protein system in that it interacts with TnC and TnI of the troponin complex and the proteins of the myofibrillar thin filament, tropomyosin and actin. In the myofibril the molecule is about 18nm long and for much its length interacts with tropomyosin. The ability of TnT to form a complex with tropomyosin is responsible for locating the troponin complex with a periodicity of 38.5nm along the thin filament of the myofibril. In addition to its structural role, TnT has the important function of transforming the TnI–TnC complex into a system, the inhibitory activity of which, on the tropomyosin–actomyosin MgATPase of the myofibril, becomes sensitive to calcium ions. Different genes control the expression of TnT in fast skeletal, slow skeletal and cardiac muscles. In all muscles, and particularly in fast skeletal, alternative splicing of mRNA produces a series of isoforms in a developmentally regulated manner. In consequence TnT exists in many more isoforms than any of the other thin filament proteins, the TnT superfamily. Despite the general homology of TnT isoforms, this alternative splicing leads to variable regions close to the N-␣and C-termini. As the isoforms have slightly different effects on the calcium sensitivity of the actomyosin MgATPase, modulation of the contractile response to calcium can occur during development and in different muscle types. TnT has recently aroused clinical interest in its potential for detecting myocardial damage and the association of mutations in the cardiac isoform with hypertrophic cardiomyopathy.

Troponin, a Ca2+-sensitive complex, regulates the motions of tropomyosin on the thin filaments in many muscles. It has three subunits, each with a different architecture and function: TnC binds Ca2+; TnI binds to actin and inhibits contraction; and TnT binds one complex to each tropomyosin molecule. The troponin complex has an elongated shape with TnC and TnI forming a globular 'head' region and TnT a long (approximately 160 A) 'tail'. TnT binds to two widely separated regions of tropomyosin: the head region of the complex is near Cys 190 of tropomyosin and the tail region is near the overlapping joint that links the tropomyosin molecules into filaments. Here we report the X-ray structure determination at 17 A resolution of glutaraldehyde-treated tropomyosin crystals in which native troponin complex or fragments of TnT have been bound. Our results show that the amino-terminal tail end of TnT spans the head-to-tail joint of the tropomyosin filaments, and that the 'head' region of the whole troponin complex binds approximately 200 A away near residues 150-180 of the tropomyosin molecule.