Remodeling muscles with calcineurin

Area of Science:

• Muscle physiology
• Cell signaling
• Molecular biology

Background:

• Calcium (Ca2+) signaling is vital for cardiac and skeletal muscle hypertrophy in response to mechanical load and other signals.
• The precise mechanisms linking cytoplasmic Ca2+ alterations to hypertrophic responses and long-term muscle gene expression changes remain unclear.

Purpose of the Study:

• To explore the role of calcineurin as a Ca2+ sensor in muscle hypertrophy.
• To elucidate how calcineurin links Ca2+ signaling to muscle gene expression reprogramming.
• To examine calcineurin's control over skeletal muscle contractile and metabolic properties, including slow muscle fiber gene activation.

Main Methods:

• Review and synthesis of existing research on Ca2+ signaling, calcineurin, and muscle gene expression.
• Analysis of the roles of NFAT and MEF2 transcription factors in calcineurin-mediated pathways.
• Development of a model for Ca2+-regulated gene expression in muscle cells.

Main Results:

• Calcineurin is proposed to act as a Ca2+ sensor, coupling prolonged Ca2+ level changes to muscle gene expression reprogramming.
• Calcineurin influences both cardiac and skeletal muscle hypertrophy.
• Calcineurin controls skeletal muscle contractile and metabolic properties by activating the slow muscle fiber-specific gene program, which is Ca2+ signaling-dependent.

Conclusions:

• Calcineurin is a key mediator of Ca2+-regulated gene expression in muscle cells.
• NFAT and MEF2 transcription factors are critical endpoints in calcineurin signaling pathways controlling muscle hypertrophy and fiber type.
• Findings have implications for pharmacologic strategies to modify cardiac and skeletal muscle function.