Insights into the velocity-dependent geometry and internal strain in accretionary wedges from analogue models

Although the brittle material in analogue models is characterized by a linear Navier-Coulomb behaviour and rate-independent deformation, the geometry and style of deformation in accretionary wedges is sensitive to shortening velocity. In this study we have constructed a series of analogue models with various shortening velocities in order to study the influence of shortening velocity on the geometry and kinematics of accretionary wedges. Model results illustrate how shortening velocity has an important influence on the geometry and kinematics of the resulting wedge. In general, for models having similar bulk shortening, the accretionary wedges with higher velocities of shortening are roughly steeper, higher and longer, as well as having larger critical wedge angles and height. It accommodates a number of foreland-vergent thrusts, larger fault spacing and displacement rates than those of low- to medium-velocity shortening, which indicates a weak velocity-dependence in geometry of the wedge. Moreover, models with a high velocity of shortening undergo larger amounts of volumetric strain and total layer-parallel shortening than models with low- to medium-velocity shortening. The former accommodate a greater development of back thrusts and asymmetric structures; a backwards-to-forwards style of wedge growth therefore occurs in the frontal zone under high-velocity shortening.

Accumulating Evidence for Increased Velocity of Airway Smooth Muscle Shortening in Asthmatic Airway Hyperresponsiveness

It remains unclear whether airway smooth muscle (ASM) mechanics is altered in asthma. While efforts have originally focussed on contractile force, some evidence points to an increased velocity of shortening. A greater rate of airway renarrowing after a deep inspiration has been reported in asthmatics compared to controls, which could result from a shortening velocity increase. In addition, we have recently shown in rats that increased shortening velocity correlates with increased muscle shortening, without increasing muscle force. Nonetheless, establishing whether or not asthmatic ASM shortens faster than that of normal subjects remains problematic. Endobronchial biopsies provide excellent tissue samples because the patients are well characterized, but the size of the samples allows only cell level experiments. Whole human lungs from transplant programs suffer primarily from poor patient characterization, leading to high variability. ASM from several animal models of asthma has shown increased shortening velocity, but it is unclear whether this is representative of human asthma. Several candidates have been suggested as responsible for increased shortening velocity in asthma, such as alterations in contractile protein expression or changes in the contractile apparatus structure. There is no doubt that more remains to be learned about the role of shortening velocity in asthma.

Ileal smooth muscle dysfunction and remodeling in cystic fibrosis

Patients with cystic fibrosis (CF) often suffer from gastrointestinal cramps and intestinal obstruction. The CF transmembrane conductance regulator (CFTR) channel has been shown to be expressed in vascular and airway smooth muscle (SM). We hypothesized that the absence of CFTR expression alters the gastrointestinal SM function and that these alterations may show strain-related differences in the mouse. The aim of this study was to measure the contractile properties of the ileal SM in two CF mouse models. CFTR−/− and CFTR+/+ mice were studied on BALB/cJ and C57BL/6J backgrounds. Responsiveness of ileal strips to electrical field stimulation (EFS), methacholine (MCh), and isoproterenol was measured. The mass and the cell density of SM layers were measured morphometrically. Finally, the maximal velocity of shortening (Vmax) and the expression of the fast (+)insert myosin isoform were measured in the C57BL/6J ileum. Ileal hyperreactivity was observed in response to EFS and MCh in CFTR−/− compared with CFTR+/+ mice in C57BL/6J background. This latter observation was not reproduced by acute inhibition of CFTR with CFTRinh172. BALB/cJ CFTR−/− mice exhibited a significant increase of SM mass with a lower density of cells compared with CFTR+/+, whereas no difference was observed in the C57BL/6J background. In addition, in this latter strain, ileal strips from CFTR−/− exhibited a significant increase in Vmax compared with control and expressed a greater proportion of the fast (+)insert SM myosin isoform with respect to total myosin. BALB/cJ CFTR−/− ilium had a greater relaxation to isoproterenol than the CFTR+/+ mice when precontracted with EFS, but no difference was observed in response to exogeneous MCh. In vivo, the lack of CFTR expression induces a different SM ileal phenotype in different mouse strains, supporting the importance of modifier genes in determining intestinal SM properties.

Intermedin (adrenomedullin-2) enhances cardiac contractile function via a protein kinase C- and protein kinase A-dependent pathway in murine ventricular myocytes

Intermedin (IMD), also called adrenomedullin-2, is a 47-amino acid peptide from the calcitonin gene-related peptide (CGRP)/adrenomedullin family of peptides. Recent studies suggest that IMD may participate in the regulation of cardiovascular function and fluid and electrolyte homeostasis. To evaluate the role of IMD on cardiomyocyte contractile function, electrically paced murine ventricular myocytes were acutely exposed to IMD, and the following indexes were determined: peak shortening (PS), time to PS, time-to-90% relengthening, and maximal velocity of shortening and relengthening. Intracellular Ca2+ was assessed using fura 2-AM fluorescent microscopy. Our results revealed that IMD (10 pM to 10 nM) significantly increased PS and maximal velocity of shortening and relengthening in ventricular myocytes, the maximal effect of which (∼46%) was somewhat comparable to those elicited by CGRP (1 nM) and adrenomedullin (100 nM). Exposure of IMD significantly shortened time-to-90% relengthening without affecting time to PS, similar to CGRP and adrenomedullin. IMD also enhanced intracellular Ca2+ release, with a maximal increase of ∼50%, and facilitated the intracellular Ca2+ decay rate. The IMD-induced effects were abolished by the protein kinase C inhibitor chelerythrine (1 μM), downregulation of protein kinase C using phorbol 12-myristate 13-acetate (1 μM), and the protein kinase A inhibitor H89 (1 μM). Our data suggest that IMD acutely augments cardiomyocyte contractile function through, at least in part, a protein kinase C- and protein kinase A-dependent mechanism.

High-dose benfotiamine rescues cardiomyocyte contractile dysfunction in streptozotocin-induced diabetes mellitus

Diabetic cardiomyopathy is characterized by cardiac dysfunction. This study was designed to examine the effect of benfotiamine, a lipophilic derivative of thiamine, on streptozotocin (STZ)-induced cardiac contractile dysfunction in mouse cardiomyocytes. Adult male FVB mice were made diabetic with a single injection of STZ (200 mg/kg ip). Fourteen days later, control and diabetic (fasting plasma glucose > 13.9 mM) mice were put on benfotiamine therapy (100 mg·kg−1·day−1 ip) for another 14 days. Mechanical and intracellular Ca2+ properties were evaluated in left ventricular myocytes using an IonOptix MyoCam system. The following indexes were evaluated: peak shortening (PS), time to PS (TPS), time to 90% relengthening (TR90), maximal velocity of shortening/relengthening, resting and rise of intracellular Ca2+ in response to electrical stimulus, sarcoplasmic reticulum (SR) Ca2+ load, and intracellular Ca2+ decay rate (τ). Two- or four-week STZ treatment led to hyperglycemia, prolonged TPS and TR90, reduced SR Ca2+ load, elevated resting intracellular Ca2+ level and prolonged τ associated with normal PS, maximal velocity of shortening/relengthening, and intracellular Ca2+ rise in response to electrical stimulus. Benfotiamine treatment abolished prolongation in TPS, TR90, and τ, as well as reduction in SR Ca2+ load without affecting hyperglycemia and elevated resting intracellular Ca2+. Diabetes triggered oxidative stress, measured by GSH-to-GSSG ratio and formation of advanced glycation end product (AGE) in the hearts. Benfotiamine treatment alleviated oxidative stress without affecting AGE or protein carbonyl formation. Collectively, our results indicated that benfotiamine may rescue STZ-induced cardiomyocyte dysfunction but not AGE formation in short-term diabetes.

Contractile responses of the rat gastrocnemius and soleus muscles to isotonic resistance exercise

Male rats were divided into control and weight-trained (WT) groups. WT rats performed squat-type exercises twice daily, 5 days/wk, for 14 wk. They averaged 36 lifts/day, with an average weight of 555 g. Muscle-to-body weight ratio (mg/g) of the soleus (Sol) was not different from control, but it increased 11 and 6% in the gastrocnemius (Gast) and plantaris, respectively ( P < 0.05). The normalized twitch tension of the in situ Sol was elevated by 21%, whereas single-skinned type I fibers from the Sol showed an increased rate constant of tension redevelopment ( Ktr) but no other contractile adaptations to WT. In contrast, the Gast type I fibers showed an increase ( P < 0.05) in maximal velocity of shortening (25%), peak power (15%), Ktr (18%), and normalized tension (7%). The Ktr and normalized tension of the Gast type IIa fibers increased by 24% ( P < 0.05) and 12% ( P < 0.05), respectively, whereas velocity and power showed a tendency to increase. Fiber size, determined by myosin ATPase histochemistry, was not different for any fiber type from the Gast or Sol. These results indicate that isotonic resistance exercise of the calf targets the Gast (type I and type IIa fibers) and has little effect on the Sol.

Mathematical description of geometric and kinematic aspects of smooth muscle plasticity and some related morphometrics

Despite considerable investigation, the mechanisms underlying the functional properties of smooth muscle are poorly understood. This can be attributed, at least in part, to a lack of knowledge about the structure and organization of the contractile apparatus inside the muscle cell. Recent observations of the plasticity of smooth muscle and of morphometry of the cell have provided enough information for us to propose a quantitative, although highly simplified, model for the geometric arrangement of contractile units and their collective kinematic functions in smooth muscle, particularly airway smooth muscle. We propose that, to a considerable extent, contractile machinery restructures upon activation of the muscle and adapts to cell geometry at the time of activation. We assume that, under steady-state conditions, the geometric arrangement of contractile units and the filaments within these units determines the kinematic characteristics of the muscle. The model successfully predicts the results of experiments on airway smooth muscle plasticity relating to maximal force generation, maximal velocity of shortening, and the variation of compliance with adapted length. The model is also concordant with morphometric observations that show an increase in myosin filament density when muscle is adapted to a longer length. The model provides a framework for design of experiments to quantitatively test various aspects of smooth muscle plasticity in terms of geometric arrangement of contractile units and the muscle's mechanical properties.