Skeletal muscle derived Musclin protects the heart during pathological overload

Area of Science:

• Cardiovascular Biology
• Skeletal Muscle Physiology
• Molecular Medicine

Background:

• Cachexia in chronic heart failure (CHF) patients is linked to poor prognosis, but its mechanisms driving disease progression are unclear.
• Myokine dysregulation from skeletal muscle wasting may exacerbate heart failure, yet specific pathways remain poorly understood.

Purpose of the Study:

• To investigate if altered myokine expression in skeletal muscle contributes to heart failure progression.
• To determine the role of the myokine Musclin, encoded by Ostn, in the context of heart failure and cachexia.

Main Methods:

• RNA sequencing of wasting skeletal muscles from mice with heart failure to identify differentially expressed genes.
• Generation of skeletal muscle-specific Ostn knockout and overexpression mouse models.
• Assessment of cardiac function, myocardial fibrosis, and molecular signaling pathways (protein kinase A and G).

Main Results:

• Reduced expression of Ostn, encoding Musclin, was observed in the skeletal muscle of mice with heart failure.
• Skeletal muscle-specific Ostn knockout exacerbated cardiac dysfunction and myocardial fibrosis.
• Overexpression of Musclin in skeletal muscle attenuated cardiac dysfunction and fibrosis.
• Musclin was found to enhance C-type natriuretic peptide (CNP) abundance, promoting cardiomyocyte contractility and inhibiting fibroblast activation.

Conclusions:

• Reduced skeletal muscle Musclin levels worsen heart failure progression and fibrosis.
• Musclin signaling, through CNP, protein kinase A, and protein kinase G, plays a protective role in the heart.
• Decreased OSTN expression in human heart failure skeletal muscle suggests Musclin augmentation as a potential therapeutic strategy.