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Bioengineered Model of Human LGMD2B Skeletal Muscle Reveals Roles of Intracellular Calcium Overload in Contractile and Metabolic Dysfunction in Dysferlinopathy.

Publication ,  Journal Article
Khodabukus, A; Prabhu, NK; Roberts, T; Buldo, M; Detwiler, A; Fralish, ZD; Kondash, ME; Truskey, GA; Koves, TR; Bursac, N
Published in: Adv Sci (Weinh)
August 2024

Dysferlin is a multi-functional protein that regulates membrane resealing, calcium homeostasis, and lipid metabolism in skeletal muscle. Genetic loss of dysferlin results in limb girdle muscular dystrophy 2B/2R (LGMD2B/2R) and other dysferlinopathies - rare untreatable muscle diseases that lead to permanent loss of ambulation in humans. The mild disease severity in dysferlin-deficient mice and diverse genotype-phenotype relationships in LGMD2B patients have prompted the development of new in vitro models for personalized studies of dysferlinopathy. Here the first 3-D tissue-engineered hiPSC-derived skeletal muscle ("myobundle") model of LGMD2B is described that exhibits compromised contractile function, calcium-handling, and membrane repair, and transcriptomic changes indicative of impaired oxidative metabolism and mitochondrial dysfunction. In response to the fatty acid (FA) challenge, LGMD2B myobundles display mitochondrial deficits and intracellular lipid droplet (LD) accumulation. Treatment with the ryanodine receptor (RyR) inhibitor dantrolene or the dissociative glucocorticoid vamorolone restores LGMD2B contractility, improves membrane repair, and reduces LD accumulation. Lastly, it is demonstrated that chemically induced chronic RyR leak in healthy myobundles phenocopies LGMD2B contractile and metabolic deficit, but not the loss of membrane repair capacity. Together, these results implicate intramyocellular Ca2+ leak as a critical driver of dysferlinopathic phenotype and validate the myobundle system as a platform to study LGMD2B pathogenesis.

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Published In

Adv Sci (Weinh)

DOI

EISSN

2198-3844

Publication Date

August 2024

Volume

11

Issue

31

Start / End Page

e2400188

Location

Germany

Related Subject Headings

  • Muscular Dystrophies, Limb-Girdle
  • Muscle, Skeletal
  • Muscle Contraction
  • Humans
  • Dysferlin
  • Calcium
  • Animals
 

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Khodabukus, A., Prabhu, N. K., Roberts, T., Buldo, M., Detwiler, A., Fralish, Z. D., … Bursac, N. (2024). Bioengineered Model of Human LGMD2B Skeletal Muscle Reveals Roles of Intracellular Calcium Overload in Contractile and Metabolic Dysfunction in Dysferlinopathy. Adv Sci (Weinh), 11(31), e2400188. https://doi.org/10.1002/advs.202400188
Khodabukus, Alastair, Neel K. Prabhu, Taylor Roberts, Meghan Buldo, Amber Detwiler, Zachary D. Fralish, Megan E. Kondash, George A. Truskey, Timothy R. Koves, and Nenad Bursac. “Bioengineered Model of Human LGMD2B Skeletal Muscle Reveals Roles of Intracellular Calcium Overload in Contractile and Metabolic Dysfunction in Dysferlinopathy.Adv Sci (Weinh) 11, no. 31 (August 2024): e2400188. https://doi.org/10.1002/advs.202400188.
Khodabukus A, Prabhu NK, Roberts T, Buldo M, Detwiler A, Fralish ZD, et al. Bioengineered Model of Human LGMD2B Skeletal Muscle Reveals Roles of Intracellular Calcium Overload in Contractile and Metabolic Dysfunction in Dysferlinopathy. Adv Sci (Weinh). 2024 Aug;11(31):e2400188.
Khodabukus, Alastair, et al. “Bioengineered Model of Human LGMD2B Skeletal Muscle Reveals Roles of Intracellular Calcium Overload in Contractile and Metabolic Dysfunction in Dysferlinopathy.Adv Sci (Weinh), vol. 11, no. 31, Aug. 2024, p. e2400188. Pubmed, doi:10.1002/advs.202400188.
Khodabukus A, Prabhu NK, Roberts T, Buldo M, Detwiler A, Fralish ZD, Kondash ME, Truskey GA, Koves TR, Bursac N. Bioengineered Model of Human LGMD2B Skeletal Muscle Reveals Roles of Intracellular Calcium Overload in Contractile and Metabolic Dysfunction in Dysferlinopathy. Adv Sci (Weinh). 2024 Aug;11(31):e2400188.
Journal cover image

Published In

Adv Sci (Weinh)

DOI

EISSN

2198-3844

Publication Date

August 2024

Volume

11

Issue

31

Start / End Page

e2400188

Location

Germany

Related Subject Headings

  • Muscular Dystrophies, Limb-Girdle
  • Muscle, Skeletal
  • Muscle Contraction
  • Humans
  • Dysferlin
  • Calcium
  • Animals