# Engineering a Human Skeletal Muscle Tissue Model of LGMD2B

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $501,861

## Abstract

Limb girdle muscular dystrophy 2B (LGMD2B) is a late-onset progressive muscular dystrophy resulting from
mutations in the dysferlin gene. Dysferlin is a membrane-associated protein, highly expressed in skeletal and
cardiac muscle fibers where it orchestrates membrane repair in response to various injuries. Currently, there are
no ongoing clinical trials or therapies to slow disease progression or cure LGMD2B. While useful for in vivo
mechanistic studies, dysferlin-deficient (BLAJ) mice, a model of LGDM2B, exhibit a mild disease phenotype
compared to humans, limiting mouse utility for translational studies. Developing a high-fidelity in vitro model of
human LGMD2B muscle would complement mouse studies and allow patient-specific disease modeling and
drug discovery. Thus, the overarching goal of this project is to engineer a novel 3D human skeletal muscle tissue
model (“myobundle”) that replicates the main structural, functional, and metabolic features of LGMD2B.
Specifically, we will utilize human iPSC lines from three healthy and three LGMD2B donors to engineer LGMD2B
myobundles that exhibit reproducible deficits in muscle contractile function, calcium homeostasis, and lipid
handling, while showing drug responses consistent with studies in BLAJ mice and LGMD2B patients. Importantly,
a defining feature of LGMD2B muscle is the ectopic fat formation suggested to occur due to adipogenic
differentiation of muscle interstitial cells (MICs). We will thus develop a novel tissue-engineered model of
intramuscular adipose tissue (IMAT) accumulation in LGMD2B muscle by co-culturing MICs isolated from
LGMD2B human muscle biopsies and iPSC-derived muscle progenitor cells. In this novel co-culture system, we
will identify pro-adipogenic factors secreted from LGMD2B muscle and study their ability to induce ectopic fat
formation. Since immune cell infiltration and biased macrophage polarization are additional defining features of
LGMD2B muscle, we will engineer co- and tri-cultured muscle-macrophage myobundles to further characterize
roles of heterocellular interactions and inflammatory milieu in injury response and fat accumulation in LGMD2B.
Finally, our preliminary studies suggest that the cholesterol metabolism in LGMD2B muscle is impaired and
contributes to the disease, which we will further study pharmacologically, biochemically, and histologically in
LGMD2B myobundles and BLAJ mice. Overall, we expect that the novel tissue-engineered model of human
LGMD2B muscle developed in this project will enable new mechanistic and pharmacological studies, eventually
leading to first clinical trials for LGMD2B.

## Key facts

- **NIH application ID:** 10903900
- **Project number:** 5R01AR082979-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Nenad Bursac
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $501,861
- **Award type:** 5
- **Project period:** 2023-08-15 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10903900

## Citation

> US National Institutes of Health, RePORTER application 10903900, Engineering a Human Skeletal Muscle Tissue Model of LGMD2B (5R01AR082979-02). Retrieved via AI Analytics 2026-06-25 from https://api.ai-analytics.org/grant/nih/10903900. Licensed CC0.

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