Integrative Physiology Methods and Results: Cardiac Mri Revealed That Genetic Inactivation of Myostatin Signaling in the Adult Murine Heart Caused Cardiac Hypertrophy and Heart Failure, Partially Recapitulating Effects of the Age-dependent Decline of the Myostatin Paralog Growth and Differentiation

Myostatin, also named growth and differentiation factor (GDF) 8, is a member of the transforming growth factor-β superfamily of growth factors and serves as a major negative regulator of skeletal muscle growth. Inactivation of myostatin by targeted deletion and by naturally occurring mutations leads to a vast increase of muscle mass in several species, including mice and human beings. Myostatin also plays a decisive role in the regulation of metabolic processes. Constitutive myostatin knockout mice show reduced adiposity, increased insulin sensitivity, and are resistant to obesity. Inactivation of myostatin in 2 genetic models of obesity led to a partial suppression of fat accumulation and normalization of glucose metabolism. The primary site of myostatin expression is skeletal muscle, although myostatin is also produced in significant amounts in fat tissue and the heart. Interestingly, myostatin is strongly upregulated under different pathological conditions of the heart (eg, myocardial infarction, hypertrophy, and heart failure), arguing for a specific role in cardiac pathophysiology. Furthermore, a recent study revealed that GDF11, which is highly similar to myostatin/GDF8, reverses age-related cardiac hypertrophy, suggesting a role of GDF family members in the restriction of compensatory cardiac growth. Yet, germ-line inactivation of myostatin yielded conflicting results, describing no effect on cardiac hypertrophy or function or reduced ejection fraction and eccentric hypertrophy. Similarly, lineage-specific deletion of myostatin in cardiac progenitor cells revealed no differences in cardiac size and function in young mice, whereas constitutive overexpression of myostatin in the heart and in the heart and skeletal muscle reduces cardiac mass and cardiomyocyte proliferation without effects on cardiac systolic function. Integrative Physiology

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