Roles of cMyBP-C phosphorylation on cardiac contractile dysfunction in db/db mice

Area of Science:

• Cardiology
• Metabolic Diseases
• Molecular Biology

Background:

• Type 2 diabetes mellitus (T2DM) is linked to cardiac dysfunction, specifically heart failure with preserved ejection fraction (HFpEF).
• The molecular underpinnings of T2DM-induced cardiomyopathy (T2DM-CM) remain largely unknown.
• Hyperphosphorylation of cardiac myosin binding protein-C is implicated in T2DM-CM pathogenesis.

Purpose of the Study:

• To elucidate the molecular mechanisms of T2DM-CM.
• To investigate the therapeutic potential of cardiac myosin inhibitors for T2DM-CM.

Main Methods:

• Utilized Lepr db/db mice as a model for T2DM-CM.
• Performed echocardiography to assess cardiac function.
• Conducted RNA-seq analysis to identify differentially regulated genes.
• Investigated the effect of mavacamten (MYK-461) on cardiac contractility in vitro.

Main Results:

• Lepr db/db mice exhibited cardiac dysfunction and left ventricular hypertrophy by 6 months.
• RNA-seq identified dysregulated genes linked to cardiac dysfunction.
• Cardiac myosin binding protein-C hyperphosphorylation was elevated in Lepr db/db hearts.
• Mavacamten significantly reduced muscle force and cardiomyocyte contractility in db/db models.

Conclusions:

• T2DM-CM is associated with cardiac myosin binding protein-C hyperphosphorylation.
• Mavacamten demonstrated efficacy in mitigating T2DM-CM progression in vitro.
• Cardiac myosin inhibitors represent a potential therapeutic strategy for T2DM-induced HFpEF.