Characterization of metabolic alterations in the lean metabolically unhealthy alpha defensin transgenic mice

Higazi, Abd Al-Roof; Maraga, Emad; Baraghithy, Saja; Udi, Shiran; Azar, Shahar; Saada, Ann; Glaser, Benjamin; Avrahami, Dana; Abdeen, Suhair; Hamdan, Zenab; Tam, Joseph; Fanne, Rami Abu

doi:10.1016/j.isci.2024.108802

iScience

2024

DOI: 10.1016/j.isci.2024.108802

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Characterization of metabolic alterations in the lean metabolically unhealthy alpha defensin transgenic mice

Abd Al-Roof Higazi,

Emad Maraga,

Saja Baraghithy

et al.

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2024

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Cited by 2 publications

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The Autophagic Activator GHF-201 Can Alleviate Pathology in a Mouse Model and in Patient Fibroblasts of Type III Glycogenosis

Mishra,

Sweetat,

Baraghithy

et al. 2024

Biomolecules

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Glycogen storage disease type III (GSDIII) is a hereditary glycogenosis caused by deficiency of the glycogen debranching enzyme (GDE), an enzyme, encoded by Agl, enabling glycogen degradation by catalyzing alpha-1,4-oligosaccharide side chain transfer and alpha-1,6-glucose cleavage. GDE deficiency causes accumulation of phosphorylase-limited dextrin, leading to liver disorder followed by fatal myopathy. Here, we tested the capacity of the new autophagosomal activator GHF-201 to alleviate disease burden by clearing pathogenic glycogen surcharge in the GSDIII mouse model Agl−/−. We used open field, grip strength, and rotarod tests for evaluating GHF-201’s effects on locomotion, a biochemistry panel to quantify hematological biomarkers, indirect calorimetry to quantify in vivo metabolism, transmission electron microscopy to quantify glycogen in muscle, and fibroblast image analysis to determine cellular features affected by GHF-201. GHF-201 was able to improve all locomotion parameters and partially reversed hypoglycemia, hyperlipidemia and liver and muscle malfunction in Agl−/− mice. Treated mice burnt carbohydrates more efficiently and showed significant improvement of aberrant ultrastructural muscle features. In GSDIII patient fibroblasts, GHF-201 restored mitochondrial membrane polarization and corrected lysosomal swelling. In conclusion, GHF-201 is a viable candidate for treating GSDIII as it recovered a wide range of its pathologies in vivo, in vitro, and ex vivo.

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The Autophagic Activator GHF-201 Can Alleviate Pathology in a Mouse Model and in Patient Fibroblasts of Type III Glycogenosis

Mishra,

Sweetat,

Baraghithy

et al. 2024

Biomolecules

View full text Add to dashboard Cite

show abstract

When Being Lean Is Not Enough: The Metabolically Unhealthy Normal Weight Phenotype and Cardiometabolic Disease

Park,

Shin,

Magkos

2024

Cardiometab Syndr J

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Characterization of metabolic alterations in the lean metabolically unhealthy alpha defensin transgenic mice

Cited by 2 publications

References 54 publications

The Autophagic Activator GHF-201 Can Alleviate Pathology in a Mouse Model and in Patient Fibroblasts of Type III Glycogenosis

The Autophagic Activator GHF-201 Can Alleviate Pathology in a Mouse Model and in Patient Fibroblasts of Type III Glycogenosis

When Being Lean Is Not Enough: The Metabolically Unhealthy Normal Weight Phenotype and Cardiometabolic Disease

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