Fast skeletal myosin binding protein-C expression exacerbates dysfunction in heart failure

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Heart Failure Pathophysiology

Background:

• Heart failure (HF) involves complex gene and protein remodeling.
• Fast skeletal myosin binding protein-C (fMyBP-C) is upregulated in diseased hearts.
• The functional impact of cardiac fMyBP-C expression is unknown.

Purpose of the Study:

• To investigate the consequences of fMyBP-C expression on cardiac function and pathology.
• To determine if fMyBP-C is sufficient to cause cardiac dysfunction.
• To assess the role of fMyBP-C in HF models.

Main Methods:

• Generated cardiac-specific fMyBP-C over-expression mice.
• Crossed fMyBP-C over-expressing mice with cardiac myosin binding protein-C (cMyBP-C) null mice.
• Utilized transverse aortic constriction (TAC) in fMyBP-C null mice to model HF.
• Employed shRNA to reduce fMyBP-C expression in HF models.

Main Results:

• Low-level fMyBP-C expression caused mild cardiac remodeling and sarcomere dysfunction.
• Exclusive fMyBP-C expression in an HF model worsened cardiac pathology.
• fMyBP-C reduction via shRNA improved cardiac function in HF.
• fMyBP-C null mice showed increased resistance to cardiac decompensation after pressure overload.
• Differential regulation of the myosin super-relaxed state by cMyBP-C and fMyBP-C was implicated.

Conclusions:

• Elevated fMyBP-C expression in diseased hearts is a pathological response.
• fMyBP-C contributes to cardiac dysfunction and exacerbates HF.
• Targeting fMyBP-C upregulation may offer a therapeutic strategy for HF.