Angiotensin II Induces Skeletal Muscle Atrophy by Activating TFEB-Mediated MuRF1 Expression

Area of Science:

• Molecular Biology
• Physiology
• Biochemistry

Background:

• Skeletal muscle wasting and cachexia are life-threatening complications of congestive heart failure (CHF).
• The renin-angiotensin aldosterone system is implicated in CHF-related muscle wasting.
• Angiotensin II (Ang II) induces skeletal muscle atrophy partly via increased muscle RING-finger-1 (MuRF1) expression, potentially involving protein kinase D1 (PKD1).

Purpose of the Study:

• To elucidate the molecular mechanisms underlying Ang II-induced skeletal muscle wasting in the context of CHF.

Main Methods:

• Utilized a cDNA expression screen to identify regulators of the MuRF1 promoter.
• Employed small interfering RNA (siRNA) to inhibit transcription factor EB (TFEB).
• Investigated the interaction and colocalization of histone deacetylase-5 (HDAC5) and TFEB, and the role of PKD1 in this interaction.
• Examined muscle wasting in mice lacking PKD1 in skeletal myocytes.

Main Results:

• Identified TFEB as a novel regulator of the human MuRF1 promoter, crucial for Ang II-induced skeletal muscle atrophy.
• Demonstrated that TFEB transcriptionally controls MuRF1 expression via E-box elements.
• Showed that inhibiting TFEB with siRNA prevented Ang II-induced MuRF1 expression and muscle atrophy.
• Found that HDAC5 binds to and colocalizes with TFEB, inhibiting TFEB-mediated MuRF1 expression.
• Revealed that PKD1 reverses HDAC5-mediated inhibition of TFEB by promoting HDAC5 nuclear export.
• Observed that mice lacking PKD1 in skeletal myocytes were resistant to Ang II-induced muscle wasting.

Conclusions:

• Propose a novel pathway: elevated Ang II in CHF activates PKD1/HDAC5/TFEB/MuRF1 to induce skeletal muscle wasting.
• This pathway offers potential therapeutic targets for preventing muscle wasting in CHF patients.