Desmin Phosphorylation Triggers Preamyloid Oligomers Formation and Myocyte Dysfunction in Acquired Heart Failure

Area of Science:

• Cardiovascular Biology
• Proteinopathies
• Molecular Cardiology

Background:

• Disrupted proteostasis is a hallmark of heart failure (HF) and other proteinopathies like Alzheimer's and Parkinson's diseases.
• The development of cardiac preamyloid oligomers (PAOs) in acquired HF remains poorly understood.
• Previous work identified increased aggregate-prone, monophosphorylated desmin in HF.

Purpose of the Study:

• To investigate if monophosphorylated desmin seeds PAOs formation in acquired HF.
• To determine if positron emission tomography (PET) can detect myocardial PAOs in non-genetic HF.
• To explore the role of desmin phosphorylation in cardiac PAOs accumulation.

Main Methods:

• Utilized a mouse model of transverse aortic constriction to induce acquired HF.
• Examined cardiac extracts from human HF patients (ischemic and non-ischemic).
• Investigated desmin aggregation in cultured cardiomyocytes.
• Employed PET imaging to detect in vivo cardiac PAOs.

Main Results:

• Toxic cardiac PAOs accumulate in the myocardium of mice with acquired HF.
• PAOs colocalize with the cytoskeletal protein desmin in HF models.
• Ser31 phosphorylated desmin shows extensive aggregation in cultured cardiomyocytes.
• Successfully detected in vivo cardiac PAOs accumulation using PET in acquired HF.

Conclusions:

• Ser31 phosphorylated desmin is a probable seed for cardiac PAOs nucleation and deposition.
• Desmin post-translational modification and misfolding offer a novel diagnostic and therapeutic target for cardiac PAOs.
• PET imaging provides a new method for measuring cardiac PAOs in acquired HF.