Skeletal muscle denervation causes skeletal muscle atrophy through a pathway that involves both Gadd45a and HDAC4

Area of Science:

• Molecular Biology
• Muscle Physiology
• Cellular Biology

Background:

• Skeletal muscle denervation leads to atrophy through complex, poorly understood molecular pathways.
• Growth arrest and DNA damage-inducible 45α (Gadd45a) mRNA is significantly upregulated following muscle denervation and is essential for atrophy.
• The precise mechanism driving Gadd45a mRNA induction post-denervation has remained elusive.

Purpose of the Study:

• To elucidate the molecular mechanism by which muscle denervation increases Gadd45a mRNA levels.
• To determine the role of histone deacetylase 4 (HDAC4) in regulating Gadd45a during denervation-induced muscle atrophy.

Main Methods:

• Utilized mouse models to investigate the role of HDAC4 in denervation-induced Gadd45a mRNA expression.
• Examined the sufficiency of forced HDAC4 expression in inducing Gadd45a mRNA.
• Assessed the downstream effects of Gadd45a, including myogenin and nicotinic acetylcholine receptor mRNA induction and muscle fiber atrophy.
• Investigated the involvement of HDAC4 and ATF4 in fasting-induced muscle atrophy for comparison.

Main Results:

• HDAC4 was identified as a key mediator for Gadd45a mRNA induction in denervated skeletal muscle.
• Forced expression of HDAC4 alone was sufficient to elevate Gadd45a mRNA in skeletal muscle.
• Gadd45a mediated downstream effects of HDAC4, including myogenin induction and muscle atrophy.
• HDAC4 was not required for fasting-induced muscle atrophy or Gadd45a expression, distinguishing it from fasting-related pathways.

Conclusions:

• HDAC4 is a critical regulator of Gadd45a in the context of denervation-induced skeletal muscle atrophy.
• Gadd45a acts as a convergence point for distinct upstream regulatory mechanisms in muscle atrophy, differing between denervation and fasting.
• This study clarifies a key molecular pathway contributing to muscle wasting following nerve damage.