Biology subjects

Richards, A. M.

Publications and source records attributed to Richards, A. M..

5 recordsLinked to original sources

bioRxiv2026

Empagliflozin preserves cardiac function and modulates metabolism in a mouse model of Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a fatal genetic disorder characterized by skeletal muscle degeneration and cardiomyopathy without a cure. This study examined the therapeutic potential of the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (EMPA) on cardiac function in the dystrophin-deficient mdx mouse model of DMD. Male mice were fed control chow or EMPA-containing chow ([~]25 mg/kg/day), and cardiac function was evaluated longitudinally by four-dimensional ultrasound imaging. EMPA did not alter left ventricular mass or chamber volume but preserved ejection fraction (EF) for 12 weeks, maintained significantly higher EF through 24 weeks, and attenuated global impairment of systolic and diastolic myocardial deformation. These functional improvements were accompanied by reduced cardiomyocyte hypertrophy and decreased expression of cardiac stress genes. EMPA reduced mitochondrial DNA damage, increased mitochondrial DNA copy number, and induced transcriptional signatures consistent with enhanced fatty acid and ketone metabolism, contributing to increased myocardial ATP content. Systemically, EMPA improved body mass trajectory, preserved relative lean mass, enhanced skeletal muscle torque, and did not adversely affect renal function. Together, these findings demonstrate that EMPA improves cardiac performance and mitochondrial integrity while enhancing myocardial energy availability in mdx mice, supporting SGLT2 inhibitors as a promising therapeutic strategy for individuals with DMD.

physiology↗

bioRxiv2026

Positive allosteric modulator of SERCA pump NDC-1171 attenuates cardiac functional decline in mouse model of Duchenne muscular dystrophy

Progressive cardiomyopathy is the leading cause of death in Duchenne muscular dystrophy (DMD). Dysregulation of calcium handling has been implicated in cardiomyopathy progression in DMD. Here we describe a therapeutic approach to improve calcium homeostasis in a mouse model of DMD using the novel therapeutic NDC-1171, which is a positive allosteric modulator of the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) pump. We synthesized NDC-1171 and treated 4-week-old D2.mdx mice (n=9) via oral gavage. A group of D2.mdx mice (n=9) and a group of DBA/2J mice (n=9; background strain) received a vehicle on the same schedule. We used ultrasound to assess left ventricular function, followed by a treadmill exhaustion test and a 4-paw grip strength test to assess skeletal muscle function. NDC-1171 attenuated cardiac functional decline in D2.mdx mice. At 16 weeks of age, left ventricular ejection fraction (LVEF) was significantly preserved in mice treated with NDC-1171 (57.7{square}{+/-}{square}0.5%) compared to mice treated with a vehicle (50.7{square}{+/-}{square}0.9%, p{square}<{square}0.05), though remained lower than background strain controls (62.4{square}{+/-}{square}0.6%). In contrast, functional behavior testing revealed no significant improvement in skeletal muscle function with treatment. These data suggest that treatment with the SERCA pump modulator NDC-1171 helps preserve cardiac function in a murine model of DMD, even as skeletal muscle function was impaired. Future work will be needed to determine if the benefits of this novel SERCA activator translate to large animal and clinical studies, but these initial results are promising and could help guide development of future treatments for pediatric patients with muscular dystrophy.

pharmacology and toxicology↗

bioRxiv2024

Functional cardiac consequences of β-adrenergic stress-induced injury in the mdx mouse model of Duchenne muscular dystrophy

Cardiomyopathy is the leading cause of death in Duchenne muscular dystrophy (DMD), however, in the mdx mouse model of DMD, the cardiac phenotype differs from that seen in DMD-associated cardiomyopathy. Although some have used pharmacologic stress to enhance the cardiac phenotype in the mdx model, many methods lead to high mortality, variable cardiac outcomes, and do not recapitulate the structural and functional cardiac changes seen in human disease. Here, we describe a simple and effective method to enhance the cardiac phenotype model in mdx mice using advanced 2D and 4D high-frequency ultrasound to monitor cardiac dysfunction progression in vivo. For our study, mdx and wild-type (WT) mice received daily low-dose (2 mg/kg/day) isoproterenol injections for 10 days. Histopathologic assessment showed that isoproterenol treatment increased myocyte injury, elevated serum cardiac troponin I levels, and enhanced fibrosis in mdx mice. Ultrasound revealed reduced ventricular function, decreased wall thickness, increased volumes, and diminished cardiac reserve in mdx mice compared to wild-type. Our findings highlight the utility of low-dose isoproterenol in mdx mice as a valuable model for exploring therapies targeting DMD-associated cardiac complications. SUMMARY STATEMENTThis work introduces an improved method to model heart failure in mouse models of Duchenne muscular dystrophy and comprehensively describes underlying cellular and physiologic mechanisms using advanced imaging techniques.

physiology↗

bioRxiv2020

Increased isoDGR motifs in plasma fibronectin are associated with atherosclerosis through facilitation of vascular fibrosis

Abnormal matrix deposition on vessels and recruitment of inflammatory cells into the arterial wall are critical events in atherosclerotic plaque formation. Fibronectin protein is a key matrix component that exhibits high levels of deamidation in atherosclerotic plaques and blood plasma, but it is unclear how this structural change impacts on endothelial function or modifies interactions with recruited leukocytes. This study aimed to determine how deamidation-induced isoDGR motifs in fibronectin influence extracellular matrix accumulation on endothelial cells, and to investigate possible effects on integrin outside-in signalling in matrix-bound monocytes which are key mediators of human atherosclerosis. Blood plasma fibrinogen and fibronectin displayed marked accumulation of isoDGR motifs in ischemic heart disease (IHD) as determined by ELISA analysis of patients undergoing coronary artery bypass grafting compared with age-matched healthy controls. Biochemical and functional assays confirmed that isoDGR-containing fibronectin promoted activation of integrin {beta}1 in monocytes and facilitated protein deposition and fibrillogenesis on endothelial cell layers. In addition, isoDGR interactions with integrins on the monocyte cell surface triggered an ERK:AP-1 signalling cascade that induced potent secretion of chemotactic mediators (including CCL2, CCL4, IL-8, and TNF), that promoted further leukocyte recruitment to the assembling plaque. Fibronectin deamidation forms isoDGR motifs that increase binding to {beta}1 integrins on the surface of endothelial cells and monocytes. Subsequent activation of integrin outside-in signalling pathways elicits a range of potent cytokines and chemokines that drive additional leukocyte recruitment to the developing atherosclerotic matrix and likely constitutes a key early event in progression to IHD.

biochemistry↗

bioRxiv2018

Large-scale whole-genome sequencing of three diverse Asian populations in Singapore

Asian populations are currently underrepresented in human genetics research. Here we present whole-genome sequencing data of 4,810 Singaporeans from three diverse ethnic groups: 2,780 Chinese, 903 Malays, and 1,127 Indians. Despite a medium depth of 13.7x, we achieved essentially perfect (>99.8%) sensitivity and accuracy for detecting common variants and good sensitivity (>89%) for detecting extremely rare variants with <0.1% allele frequency. We found 89.2 million single-nucleotide polymorphisms (SNPs) and 9.1 million small insertions and deletions (INDELs), more than half of which have not been cataloged in dbSNP. In particular, we found 126 common deleterious mutations (MAF>0.01) that were absent in the existing public databases, highlighting the importance of local population reference for genetic diagnosis. We describe fine-scale genetic structure of Singapore populations and their relationship to worldwide populations from the 1000 Genomes Project. In addition to revealing noticeable amounts of admixture among three Singapore populations and a Malay-related novel ancestry component that has not been captured by the 1000 Genomes Project, our analysis also identified some fine-scale features of genetic structure consistent with two waves of prehistoric migration from south China to Southeast Asia. Finally, we demonstrate that our data can substantially improve genotype imputation not only for Singapore populations, but also for populations across Asia and Oceania. These results highlight the genetic diversity in Singapore and the potential impacts of our data as a resource to empower human genetics discovery in a broad geographic region.

genetics↗