Identification of a KLF5-dependent program and drug development for skeletal muscle atrophy

Area of Science:

• Molecular biology
• Physiology
• Genetics

Background:

• Skeletal muscle atrophy, driven by aging, disuse, and cachexia, lacks sufficient understanding of its molecular mechanisms.
• This knowledge gap hinders the development of effective pharmacological treatments and preventive strategies for muscle wasting.

Purpose of the Study:

• To identify key molecular mediators of early skeletal muscle atrophy.
• To investigate the role of Krüppel-like factor 5 (KLF5) in muscle atrophy.
• To evaluate the therapeutic potential of KLF5 inhibition using Am80.

Main Methods:

• In vitro studies using myotubes treated with dexamethasone or simulated microgravity.
• In vivo studies involving skeletal muscle-specific Klf5 deletion in mice subjected to mechanical unloading.
• Transcriptome and genome-wide chromatin accessibility analyses.
• Administration of Am80 (KLF5 inhibitor) in vitro and in vivo.

Main Results:

• KLF5 expression was upregulated in atrophying myotubes as an early response.
• Skeletal muscle-specific deletion of Klf5 attenuated muscle atrophy induced by mechanical unloading.
• KLF5 was found to regulate atrophy-related programs, including proteolysis, in coordination with Foxo1.
• Am80 suppressed muscle atrophy in vitro and ameliorated it in mice.
• Human data showed increased KLF5 expression with aging and sarcopenia, correlating with atrophy-related genes.

Conclusions:

• Krüppel-like factor 5 (KLF5) is a key transcriptional regulator mediating early skeletal muscle atrophy.
• Pharmacological inhibition of KLF5 with Am80 represents a potential preventive and therapeutic strategy for muscle wasting conditions.
• KLF5's role in coordinating metabolic changes and proteolysis highlights its central importance in muscle homeostasis.