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Autophagy activation via BAG3 gene therapy improves phenotype in a mouse model of LGMD1A

Burcak Ozes1, Lingying Tong1, Kyle Moss1

  • 1Center for Gene Therapy, The Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH 43205, USA.

Molecular Therapy. Advances
|May 15, 2026
PubMed

Insights

Overexpressing BCL2-associated athanogene 3 (BAG3) protein in mice with myotilinopathy reduced protein aggregates and improved muscle function. This suggests BAG3 may be a therapeutic target for protein aggregate myopathies.

Area of Science:

  • Muscle biology
  • Proteinopathies
  • Autophagy

Background:

  • Myofibrillar myopathies (MFMs) involve protein aggregates and muscle fiber disintegration.
  • Myotilinopathy (MFM3/LGMD1A) stems from myotilin mutations, with impaired protein degradation pathways.
  • The autophagy-lysosome pathway (ALP) handles aggregate clearance when the ubiquitin-proteasome system is overloaded.

Purpose of the Study:

  • To evaluate the therapeutic potential of overexpressing human BAG3 (hBAG3) in a mouse model of myotilinopathy (TgT57I mice).
  • To assess if BAG3 overexpression can reduce muscle aggregate burden and improve muscle function.

Main Methods:

  • Systemic delivery of adeno-associated virus carrying hBAG3 (AAVrh74.tMCK.hBAG3) into TgT57I mice.
  • Functional assessments included rotarod, treadmill running, grip strength, and maximum tetanic response.
  • Histological and molecular analyses examined myotilin aggregate levels and autophagy markers.

Main Results:

  • hBAG3-treated mice showed significant improvements in all functional measures compared to controls.
  • Myotilin aggregate burden was substantially reduced, and autophagy levels were normalized post-treatment.
  • Endogenous Bag1/Bag3 ratio was normalized in hBAG3-treated mice, indicating adaptive response.

Conclusions:

  • Overexpression of BAG3 effectively reduces myotilin aggregate burden in a mouse model of myotilinopathy.
  • BAG3-based gene therapy demonstrates therapeutic potential for treating protein aggregate myopathies.
  • Restoring protein homeostasis via BAG3 modulation offers a promising therapeutic strategy.
Keywords:
AAVBAG1BAG3MFM3autophagymyofibrillar myopathymyotilinopathyprotein accumulationprotein aggregate myopathy

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