Biology subjects

Riddell, D. O.

Publications and source records attributed to Riddell, D. O..

3 recordsLinked to original sources

bioRxiv2026

A positively selected microRNA controls a reversible aging program in striated muscle

Aging is the primary risk factor for most chronic diseases and is characterized in striated muscle by progressive functional decline, mitochondrial dysfunction, and chronic inflammation. The miR-128-1 locus resides within a positively selected haplotype on chromosome 2q21.3 associated with variation in grip strength, pulmonary function, and cardiometabolic traits in humans. Here, we show that antisense oligonucleotide-mediated inhibition of miR-128-3p restores muscle mass and function in aged mice, improves cardiac function while limiting adverse remodeling following myocardial infarction, and ameliorates skeletal and cardiac muscle pathology in mouse and pig models of Duchenne muscular dystrophy. Across these contexts, miR-128-3p inhibition induces a conserved transcriptional response characterized by activation of mitochondrial programs and suppression of inflammatory and fibrotic signaling, resembling the effects of established longevity interventions. These findings identify miR-128-3p as a regulator of a conserved aging-associated program and establish its inhibition as a strategy to restore tissue function across aging-related muscle pathologies.

molecular biology↗

bioRxiv2025

Progression of the cardiac phenotype of the DE50-MD dog model of Duchenne Muscular Dystrophy, corroborating results of cardiac magnetic resonance imaging with pathology up to 36 months of age.

Cardiomyopathy is an expected consequence of the invariably fatal, X-linked muscle-wasting disease, Duchenne Muscular Dystrophy, (DMD) but onset and progression vary between individuals. Cardiac magnetic resonance imaging (CMR) is invaluable for identification of subclinical myocardial abnormalities, to stratify disease and to identify patients needing early therapeutic intervention. The dystrophin-deficient DE50-MD canine model harbours a mutation in the major hot spot region for mutations in DMD patients and mimics the preclinical cardiac and skeletal muscle of DMD boys. We performed serial parametric (T1, T2 and extracellular volume) mapping and late gadolinium enhancement (LGE) studies to characterise myocardial pathology in 15-to-36-month-old DE50-MD, (n=8) and wild type (WT, n=6) dogs. In 6/8 DE50-MD dogs left ventricular (LV) subepicardial LGE identified myocardial fibrofatty infiltration, (confirmed with histopathology post-mortem) with the characteristic distribution reported in DMD cardiomyopathy. Parametric mapping techniques exposed diffuse myocardial pathology that was most pronounced in DE50-MD dogs of 30 months and older and supported extracellular matrix expansion due to fibrosis, with or without regional myocardial oedema and /or fatty infiltration in individual dogs. All CMR markers of fibrosis worsened with age in DE50-MD dogs and paralleled deterioration in ventricular function evaluated with conventional and speckle tracking (circumferential strain) echocardiography, the burden of fragmented QRS complexes in 12-lead electrocardiography studies and the severity of pathological lesions. LGE and parametric mapping studies accurately identified a spectrum of myocardial abnormalities encountered in young DE50-MD dogs, further validating the relevance of these dogs as a preclinical model of DMD cardiomyopathy.

pathology↗

bioRxiv2025

The preclinical cardiac phenotype of the DE50-MD dog model of Duchenne muscular dystrophy.

Cardiomyopathy is the leading cause of death in the X-linked disorder, Duchenne Muscular Dystrophy (DMD) yet optimal management strategies remain undetermined. Advances in the search for novel DMD treatments, particularly at cell and molecular levels, rely heavily on the use of translational animal models. It is crucial that these models faithfully recapitulate the human clinical phenotype to best expedite the development of promising treatments. We sought comprehensively to describe the cardiac phenotype of DE50-MD dogs, a novel dystrophin-deficient model that harbours a mutation within the principal DMD mutational hotspot. Cardiac magnetic resonance imaging and echocardiographic studies were performed at approximately 12-week intervals in male, 3- to 18-month-old DE50-MD (n=17) and age-matched littermates, wild type (WT, n=14) dogs. Late gadolinium enhancement (LGE) imaging was performed in a subpopulation of DE50-MD (n=10) and WT (n=11) dogs aged 9 to 18 months. The DE50-MD dogs had smaller left ventricular (LV) mass and LV dimensions than WT dogs. While global ventricular systolic function was preserved, DE50-MD dogs showed early differences in strain and strain rate parameters. Only DE50-MD dogs demonstrated LGE (3/8 dogs studied at 18 months); the subepicardial to transmural, mid-to-basal LV LGE distribution resembling that of DMD patients and of other dystrophic dog models. Histopathological assessment confirmed that LGE corresponded to fibrofatty myocardial scarring, as described in DMD patients and other canine models of dystrophin-deficient cardiomyopathy. The DE50-MD early preclinical cardiac phenotype shares key features of DMD cardiomyopathy prior to onset of global LV systolic dysfunction. Their disproportionately low LV volume to mass supports possible combined physiological hypotrophy and tonic contraction in affected animals.

pathology↗