What question did this study set out to answer?

To elucidate why mutations in the ubiquitously expressed VMA21 chaperone selectively trigger skeletal muscle disease in X-linked myopathy with excessive autophagy (XMEA).

September 26, 2023Human Molecular GeneticsOpen Access

Identification of a muscle-specific isoform of VMA21 as a potent actor in X-linked myopathy with excessive autophagy pathogenesis

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Authors

ICIlaria CocchiararoUniversity of Geneva OCOlivia CattaneoUniversity of Geneva JRJayasimman RajendranUniversity of Geneva

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Implication

Molecular study reveals a muscle-specific VMA21 isoform depleted in muscle cells, indicating how ubiquitous mutations cause selective X-linked myopathy.

Key Points

To elucidate why mutations in the ubiquitously expressed VMA21 chaperone selectively trigger skeletal muscle disease in X-linked myopathy with excessive autophagy (XMEA).
Characterized VMA21 transcript and protein expression during mouse and human myogenic precursor differentiation, as well as during mouse muscle development, regeneration, and denervation.
Assessed subcellular localization, vacuolar ATPase interaction, and autophagic flux responses following VMA21 isoform overexpression and in the presence of XMEA-associated mutations in vitro and in vivo.
Identified a novel, long protein isoform (VMA21-120) that is predominantly expressed in skeletal muscle and accumulates during myogenic differentiation, regeneration, and denervation, unlike the ubiquitous short isoform (VMA21-101).
Observed that both VMA21-101 and VMA21-120 localize to the sarcoplasmic reticulum and interact with vacuolar ATPase, but modulating autophagy did not substantially change their expression levels.
Demonstrated that XMEA-associated pathogenic mutations cause the combined depletion of VMA21-101 and loss of VMA21-120 expression in muscle cells.

Cite This Study

Cocchiararo et al. (2023) studied this question.

synapsesocial.com/papers/6aa8e7c3d75aeabedda33305 https://doi.org/10.1093/hmg/ddad164

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Implication

Molecular study reveals a muscle-specific VMA21 isoform depleted in muscle cells, indicating how ubiquitous mutations cause selective X-linked myopathy.

Identification of a muscle-specific isoform of VMA21 as a potent actor in X-linked myopathy with excessive autophagy pathogenesis

Discussion

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Implication

Key Points

Cite This Study

Identification of a muscle-specific isoform of VMA21 as a potent actor in X-linked myopathy with excessive autophagy pathogenesis

Discussion

Member takes

Implication

Key Points

Cite This Study

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