Magnetic resonance quantification of skeletal muscle lipid infiltration in a humanized mouse model of Duchenne muscular dystrophy

Khattri, Ram B.; Batra, Abhinandan; Matheny, Michael; Hart, Cora C.; Henley-Beasley, Spencer C; Hammers, David W.; Zeng, Huadong; White, Zoe; Ryan, Terence E.; Barton, Elisabeth R.; Bernatchez, Pascal; Walter, Glenn A.

doi:10.1002/nbm.4869

Cited by 6 publications

(6 citation statements)

References 49 publications

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“…The triceps brachii is one of the muscles that show the most exacerbation, along with the gastrocnemius muscle, whereas only a mild exacerbation of mdx-associated cardiac dysfunction was observed (Table 2). Advanced MRI/MRS imaging confirmed that the extreme fatty tissue deposition of mdx/ApoE KO mice resembles that observed clinically in DMD muscle but typically absent in mdx mice [67]. Surprisingly, no exacerbation of diaphragm fibrosis was observed in mdx/ApoE KO mice.…”

Section: Dmd Modeling and Lipoprotein Metabolism -The Mdx/apoe Ko Mousesupporting

confidence: 53%

Humanization of the mdx Mouse Phenotype for Duchenne Muscular Dystrophy Modeling: A Metabolic Perspective

Donen¹,

Milad²,

Bernatchez³

2023

JND

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Duchenne muscular dystrophy (DMD) is a severe form of muscular dystrophy (MD) that is characterized by early muscle wasting and lethal cardiorespiratory failure. While the mdx mouse is the most common model of DMD, it fails to replicate the severe loss of muscle mass and other complications observed in patients, in part due to the multiple rescue pathways found in mice. This led to several attempts at improving DMD animal models by interfering with these rescue pathways through double transgenic approaches, resulting in more severe phenotypes with mixed relevance to the human pathology. As a growing body of literature depicts DMD as a multi-system metabolic disease, improvements in mdx-based modeling of DMD may be achieved by modulating whole-body metabolism instead of muscle homeostasis. This review provides an overview of the established dual-transgenic approaches that exacerbate the mild mdx phenotype by primarily interfering with muscle homeostasis and highlights how advances in DMD modeling coincide with inducing whole-body metabolic changes. We focus on the DBA2/J strain-based D2.mdx mouse with heightened transforming growth factor (TGF)-β signaling and the dyslipidemic mdx/apolipoprotein E (mdx/ApoE) knock-out (KO) mouse, and summarize how these novel models emulate the metabolic changes observed in DMD.

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Section: Dmd Modeling and Lipoprotein Metabolism -The Mdx/apoe Ko Mousesupporting

confidence: 53%

Humanization of the mdx Mouse Phenotype for Duchenne Muscular Dystrophy Modeling: A Metabolic Perspective

Donen¹,

Milad²,

Bernatchez³

2023

JND

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“…The regeneration of limb muscles has been shown to restore normal muscle structure, whereas the DIA is subject to progressive degeneration and fibrosis formation and shows a pathology similar to that of DMD patients [30,31]. However, it is noteworthy that the mdx mouse fails to fully replicate the severity of the fibro-fatty pathology seen in human DMD [32].…”

Section: Discussionmentioning

confidence: 99%

Expression of the Pro-Fibrotic Marker Periostin in a Mouse Model of Duchenne Muscular Dystrophy

Trundle,

Cernisova,

Boulinguiez

et al. 2024

Biomedicines

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Duchenne muscular dystrophy (DMD) is characterised by fibrotic tissue deposition in skeletal muscle. We assessed the role of periostin in fibrosis using mdx mice, an established DMD murine model, for which we conducted a thorough examination of periostin expression over a year. RNA and protein levels in diaphragm (DIA) muscles were assessed and complemented by a detailed histological analysis at 5 months of age. In dystrophic DIAs, periostin (Postn) mRNA expression significantly exceeded that seen in wildtype controls at all timepoints analysed, with the highest expression at 5 months of age (p < 0.05). We found Postn to be more consistently highly expressed at the earlier timepoints compared to established markers of fibrosis like transforming growth factor-beta 1 (Tgf-β1) and connective tissue growth factor (Ctgf). Immunohistochemistry confirmed a significantly higher periostin protein expression in 5-month-old mdx mice compared to age-matched healthy controls (p < 0.01), coinciding with a significant fibrotic area percentage (p < 0.0001). RT-qPCR also indicated an elevated expression of Tgf-β1, Col1α1 (collagen type 1 alpha 1) and Ctgf in mdx DIAs compared to wild type controls (p < 0.05) at 8- and 12-month timepoints. Accordingly, immunoblot quantification demonstrated elevated periostin (3, 5 and 8 months, p < 0.01) and Tgf-β1 (8 and 12 months, p < 0.001) proteins in the mdx muscle. These findings collectively suggest that periostin expression is a valuable marker of fibrosis in this relevant model of DMD. They also suggest periostin as a potential contributor to fibrosis development, with an early onset of expression, thereby offering the potential for timely therapeutic intervention and its use as a biomarker in muscular dystrophies.

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“…However, the non-statin cholesterol-lowering agent ezetimibe showed promise in mouse models of dystrophinopathy and dysferlinopathy 43 . Increased lipids are also not a solution, as they exacerbate the muscular dystrophy phenotype 44,45 . These studies indicate that direct manipulation of lipid levels does not clearly show promise, at this time, as a therapeutic strategy for muscular dystrophy.…”

Section: Discussionmentioning

confidence: 99%

Effects of HMGCR deficiency on skeletal muscle development

Gunasekaran,

Littel,

Wells

et al. 2024

Preprint

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Pathogenic variants in HMGCR were recently linked to a limb-girdle muscular dystrophy (LGMD) phenotype. The protein product HMG CoA reductase (HMGCR) catalyzes a key component of the cholesterol synthesis pathway. The two other muscle diseases associated with HMGCR, statin-associated myopathy (SAM) and autoimmune anti-HMGCR myopathy, are not inherited in a Mendelian pattern. The mechanism linking pathogenic variants in HMGCR with skeletal muscle dysfunction is unclear. We knocked down Hmgcr in mouse skeletal myoblasts, knocked down hmgcr in Drosophila, and expressed three pathogenic HMGCR variants (c.1327C>T, p.Arg443Trp; c.1522_1524delTCT, p.Ser508del; and c.1621G>A, p.Ala541Thr) in Hmgcr knockdown mouse myoblasts. Hmgcr deficiency was associated with decreased proliferation, increased apoptosis, and impaired myotube fusion. Transcriptome sequencing of Hmgcr knockdown versus control myoblasts revealed differential expression involving mitochondrial function, with corresponding differences in cellular oxygen consumption rates. Both ubiquitous and muscle-specific knockdown of hmgcr in Drosophila led to lethality. Overexpression of reference HMGCR cDNA rescued myotube fusion in knockdown cells, whereas overexpression of the pathogenic variants of HMGCR cDNA did not. These results suggest that the three HMGCR-related muscle diseases share disease mechanisms related to skeletal muscle development.

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Magnetic resonance quantification of skeletal muscle lipid infiltration in a humanized mouse model of Duchenne muscular dystrophy

Cited by 6 publications

References 49 publications

Humanization of the mdx Mouse Phenotype for Duchenne Muscular Dystrophy Modeling: A Metabolic Perspective

Humanization of the mdx Mouse Phenotype for Duchenne Muscular Dystrophy Modeling: A Metabolic Perspective

Expression of the Pro-Fibrotic Marker Periostin in a Mouse Model of Duchenne Muscular Dystrophy

Effects of HMGCR deficiency on skeletal muscle development

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