Biology subjects

Ward, M.-L.

Publications and source records attributed to Ward, M.-L..

3 recordsLinked to original sources

bioRxiv2025

The absence of collagen VI reduces systolic function but paradoxically increases Ca2+ release in the rat heart

Collagen VI has recently been strongly linked to poor outcomes in heart failure with preserved ejection fraction through increased endotrophin, a collagen VI-derived signalling molecule linked to fibrotic remodelling in cardiovascular disease. The mutation of collagen VI can result in Ullrich congenital muscular dystrophy and Bethlem myopathy, pointing to critical function in muscle physiology. However, the role of collagen VI in the heart is poorly understood. In human heart failure with reduced ejection fraction, collagen VI is increased within the remodelled T-tubules, suggesting a possible role in tubular structure and Ca2+ dynamics. To test this hypothesis, a global knockout of the collagen VI alpha 1 gene (Col6a1-/-) was generated in the rat. T-tubule structure and ryanodine receptor cluster organisation were unchanged, but echocardiography demonstrated reduced systolic function. Paradoxically, isolated cardiomyocytes from the Col6a1-/- rat had increased Ca2+ transient amplitude and increased sarcoplasmic reticulum Ca2+ load. {beta}-adrenergic stimulation further increased Ca2+ transient amplitude and was associated with diastolic Ca2+ release events in Col6a1-/- cardiomyocytes. The disturbed Ca2+ dynamics are remarkedly similar to defects found in cardiac myocytes of the MDX mouse that has non-functional dystrophin protein. Together, these data suggest that collagen VI contributes to regulation of Ca2+ signalling in the heart through its linkage to the dystrophin-glycoprotein complex.

physiology↗

bioRxiv2025

Metabolite-sensitive cross-bridge models of human atria reveal the impact of diabetes on muscle mechanoenergetics

Type 2 diabetes is associated with a range of adverse health outcomes, including metabolic dysfunction and increased risk of heart failure. Although the interactions between diabetes and heart disease are complex and incompletely understood, they can be more effectively investigated using multiscale, biophysically-based models of the underlying physiological processes. In this study, experimental data from non-diabetic and diabetic human atrial muscles were used to develop metabolite-sensitive cross-bridge models representing each group. The parameter-isation of these cross-bridge models revealed that reduced muscle stress development and a leftward shift of the complex modulus measured in the diabetic muscles could be attributed to reduced cross-bridge stiffness and slower cross-bridge detachment rates, respectively. These cross-bridge models were also integrated into muscle models to investigate the effects of diabetic cross-bridge function, Ca2+ handling and altered metabolite availability on isometric and physiological work-loop contractions. The diabetic model produced isometric twitches with lower amplitude and prolonged duration and, in response to lowered ATP concentration, the diastolic stress increased notably. In work-loop simulations, the diabetic model exhibited slower shortening, reduced work output and lower power of shortening. However, it was also more efficient and had a less pronounced negative response to increases in Pi concentration. These simulations demonstrate that while experimentally measured differences in diabetic cardiac tissues can lead to impaired function during physiological contractions, they may also offer compensatory advantages. The insights of this study offer clear mechanisms of mechanoenergetic dysfunction in diabetic heart muscle, identifying potential therapeutic targets to improve cardiac outcomes for individuals with diabetes.

physiology↗

bioRxiv2020

Mechanical stimulation of endocardial Purkinje fibres can trigger ventricular arrhythmias

Acute ventricular dilation can evoke mechanically-induced arrhythmias, our study investigated whether Purkinje fibres (PFs) may play a role. Changes in left ventricular (LV) pressure and pseudo-ECGs were measured in isolated, Langendorff-perfused, male Wistar rat hearts in sinus rhythm. The LV endocardial surface was irrigated with experimental agents, via an indwelling catheter. Mechanically-induced arrhythmias were triggered by LV lumen inflation (100l in 2s) via an indwelling balloon. Arrhythmias occurred as the LV volume was increased and spontaneously ceased within 20s of the onset of LV inflation. Arrhythmias were indexed as an increase in the standard deviation of all R-R intervals (SDRR), the number of ectopic activations and the period of these activations. Following 10s LV endocardial irrigation with Lugols solution (IK/I2) to chemically ablate surface PFs or with 0 Na+ Tyrode, there was a statistically significant attenuation of mechanically-induced arrhythmias. Lugols reduced the mechanically-induced increase in SDRR (Tyrode pre-stretch 3.5{+/-}1.7ms to 113.8{+/-}15.1ms during stretch vs Lugol pre-stretch 3.3{+/-}0.5ms to 39.9{+/-}14.5ms during stretch n=8, P < 0.05). There was also a reduction in the number (21.2{+/-}2.0 to 1.5{+/-}0.7, P<0.001) and period (5.9{+/-}0.71s to 1.7{+/-}0.85s, P< 0.01) of ectopic activations. The experiment was repeated using LV lumen irrigation with either 1{micro}M GsMTx4, a peptide that blocks stretch-activated channels or 50{micro}M 9-Phenanthrol (9-Phen), a blocker of TRPM4 channels. GsMTx4 did not attenuate mechanically-activated arrhythmias while 9-Phen had a partial effect. 9-Phen statistically reduced the number and period of ectopic activations but did not attenuate the mechanically-induced increase in SDRR (n=6-11 for each intervention). In further studies, in situ focal mechanical stimulation of individual PFs, caused ectopic activations, in each of 4 sheep LV preparations (0.2{+/-}0.1 ectopics in 10s pre-mechanical stimulation vs 2.1{+/-}0.2 ectopics in 10s during mechanical stimulation, P<0.001). We interpret our observations in rat and sheep hearts as evidence for a role of PFs in the generation of some mechanically-induced arrhythmia.

physiology↗