Modeling Reduced Contractility and Stiffness Using iPSC-Derived Cardiomyocytes Generated From Female Becker Muscular...

Area of Science:

• Cardiovascular Research
• Genetics and Genomics
• Stem Cell Biology

Background:

• Becker muscular dystrophy (BMD) is a genetic disorder primarily affecting males, but female carriers can experience cardiac complications.
• Advanced heart failure (HF) in a female BMD carrier was linked to a potential second-hit genetic variant.
• The procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 (PLOD3) gene was investigated as a candidate modifier.

Purpose of the Study:

• To investigate the role of a PLOD3 variant as a second hit in the pathogenesis of advanced heart failure (HF) in a female Becker muscular dystrophy (BMD) carrier.
• To elucidate the functional impact of the PLOD3 variant on cardiac function using patient-derived cells.

Main Methods:

• Established isogenic induced pluripotent stem cells (iPSCs) expressing wild-type DMD, a specific DMD deletion (Δ45-48-DMD), or Δ45-48-DMD with corrected PLOD3 variant.
• Utilized microforce testing on 3-dimensional self-organized tissue rings (SOTRs) derived from iPSC-cardiomyocytes (iPSC-CMs).
• Assessed collagen synthesis in iPSC-CMs.

Main Results:

• Correction of the heterozygous PLOD3 variant did not restore reduced contractile force in Δ45-48-DMD SOTRs.
• Correction of the PLOD3 variant significantly recovered reduced cardiac stiffness in Δ45-48-DMD SOTRs.
• The PLOD3 variant correction restored normal collagen synthesis in iPSC-CMs.

Conclusions:

• A PLOD3 variant acts as a modifier, influencing cardiac stiffness and collagen synthesis in the context of Becker muscular dystrophy (BMD).
• This study reveals a potential pathogenic mechanism for advanced heart failure (HF) in female BMD carriers involving PLOD3.
• PLOD3 variants should be considered in the genetic assessment of female BMD carriers presenting with cardiac dysfunction.