Biology subjects

Gordish-Dressman, H.

Publications and source records attributed to Gordish-Dressman, H..

3 recordsLinked to original sources

bioRxiv2026

The D2-mdx mouse as a preclinical model for Duchenne muscular dystrophy: a natural history study across two independent sites

IntroductionThe quality of preclinical studies for rare diseases, such as Duchenne muscular dystrophy (DMD), relies on the availability of comprehensive natural disease history data. In addition to the classic BL10-mdx mouse, in recent years, the D2-mdx model has increasingly been used as an alternative model due to its reportedly more severely impaired phenotype. To improve our understanding of disease progression in these two DMD models, we conducted a comprehensive natural history study. Materials and MethodsThis involved a cross-sectional analysis of key in vivo and ex vivo outcome measures performed in two independent laboratories, using the same study setup in compliance with TREAT-NMD Standard Operating Procedures (SOPs), while also taking advantage of site-specific expertise. Globally, largely comparable results were obtained across the two study sites. ResultsBody composition showed pronounced differences between the strains, with BL10-mdx mice displaying a hypertrophic and D2-mdx mice displaying an atrophic phenotype. Dystrophic mice of each strain exhibited significant alterations of disease-relevant indices related to muscle functionality and integrity, mostly worsening with age, in comparison to their wildtypes. Cardiac function was affected earlier and more severely in D2-mdx mice. DiscussionNotably, for some parameters, genetic-background related differences were observed, emphasizing the need to include control groups with matching genetic backgrounds in experimental designs. ConclusionsCollectively, our natural history study provides benchmark data for these two mdx mouse strains to guide model selection for preclinical DMD studies, allowing accurate data interpretation. HighlightsO_LIDistinct body composition phenotypes: BL10-mdx mice exhibit pseudohypertrophy while D2-mdx mice display pronounced atrophy. C_LIO_LIEarlier cardiac dysfunction in D2-mdx: D2-mdx mice develop reduced ejection fraction and stroke volume from 28 weeks, while BL10-mdx only at 52 weeks. C_LIO_LIGenetic background-dependent variations: Intrinsic deficits in wildtype D2 mice demonstrate that genetic background influences outcome measures independent of dystrophic pathology. C_LIO_LIComparable ex vivo muscle physiology: Despite divergent in vivo phenotypes, isolated muscle contractile parameters show similar impairment in both dystrophic models. C_LIO_LIMulti-site standardized validation: Cross-sectional study at two independent laboratories following harmonized TREAT-NMD Standard Operating Procedures. C_LI

pharmacology and toxicology↗

bioRxiv2025

Muscle Strength and Size Relationships with Unilateral Progressive Resistance Training

PurposeThis study defines correlative and causal relationships between muscle strength and size before and after unilateral resistance training (RT) in a large cohort of healthy adults, focusing on sex differences within these relationships. MethodsResults from 1233 participants (504 males and 729 females) in a retrospective analysis were included. Maximal voluntary isometric contraction strength (MVC), one-repetition maximum strength (1RM), biceps cross-sectional area (CSA) and elbow flexor volume (VOL) measures of the non-dominant and dominant arm were evaluated from baseline and after 12-wk RT twice per week. Correlations of MVC and VOL and 1RM and VOL were calculated in the whole cohort and within each sex independently. Causal analysis modeling was used to infer mechanistic relationships among variables. ResultsAbsolute muscle strength and size related to one another both at baseline and following training, however correlation strength in each sex were weak. After RT, MVC relative change and VOL relative change correlations were correlated for the whole cohort (r=0.16; p<0.001) and females (r=0.18; p<0.001), but not in males (r=0.11; p=0.07). No significant correlations for relative change in 1RM and VOL were observed for the whole cohort or within sex. Causal discovery determined that change in VOL caused significant change in 1RM (but not MVC) and age was identified as a potential cause. ConclusionsSex differences occur in muscle size and strength relationship adaptations following resistance training, most notably the absence of significant relationships between relative size and strength changes in men. Simpsons paradox bias, where assessing the combined data of males and females (also affecting overall sample size) affects identifies patterns differently than assessing relationships within each sex, may partially explain our findings.

physiology↗

bioRxiv2021

Nonsense-associated alternative splicing as a putative reno-protective mechanism in Pkhd1cyli/Pkhd1cyli mutant mice

Autosomal recessive polycystic kidney disease (ARPKD) is a hereditary hepato-renal fibrocystic disorder and a significant genetic cause of childhood morbidity and mortality. Mutations in the Polycystic Kidney and Hepatic Disease 1 (PKHD1) gene cause all typical forms of ARPKD. Several mouse strains carrying diverse genetically engineered disruptions in the orthologous Pkhd1 gene have been generated. The current study describes a novel spontaneous mouse recessive mutation causing a cystic liver phenotype resembling the hepato-biliary disease characteristic of human ARPKD. Here we describe mapping of the cystic liver mutation to the Pkhd1 interval on Chromosome 1 and identification of a frameshift mutation within Pkhd1 exon 48 predicted to result in premature translation termination. Mice homozygous for the new mutation, symbollzed Pkhd1cyli, lack renal pathology, consistent with previously generated Pkhd1 mouse mutants that fail to recapitulate human kidney disease. We have identified a profile of alternatively spliced Pkhd1 renal transcripts that are distinct in normal versus mutant mice. The Pkhd1 transcript profile in mutant kidneys is consistent with predicted outcomes of nonsense-associated alternative splicing (NAS) and nonsense mediated decay (NMD). Overall levels of Pkhd1 transcripts in mutant mouse kidneys were reduced compared to kidneys of normal mice, and Pkhd1 encoded protein in mutant kidneys was undetectable by immunoblotting. We suggest that in Pkhd1cyli/Pkhd1cyli (cyli) mice, mutation-promoted Pkhd1 alternative splicing in the kidney yields transcripts encoding low-abundance protein isoforms lacking exon 48 encoded amino acid sequences that are sufficiently functional so as to attenuate expression of a renal cystic disease phenotype.

genetics↗