Effects of Class II-Selective Histone Deacetylase Inhibitor on Neuromuscular Function and Disease Progression in...

Area of Science:

• Neuroscience
• Epigenetics
• Molecular Biology

Background:

• Epigenetic deregulation, specifically transcriptome alterations, is implicated in amyotrophic lateral sclerosis (ALS) pathogenesis.
• Pan-histone deacetylase (HDAC) inhibitors have shown promise in preclinical ALS models but failed in clinical trials, suggesting a need for greater selectivity.
• The role of specific HDAC classes in ALS, particularly in motor neurons and skeletal muscle, requires further investigation.

Purpose of the Study:

• To investigate the therapeutic potential of a selective HDAC Class II inhibitor, MC1568, in the SOD1G93A mouse model of ALS.
• To determine the effects of MC1568 on disease progression, motor neuron survival, and skeletal muscle function.
• To elucidate the molecular mechanisms underlying MC1568's effects on neuromuscular integrity.

Main Methods:

• Treatment of SOD1G93A mice with the selective HDAC Class II inhibitor MC1568.
• Assessment of disease evolution, motor neuron survival, and skeletal muscle function.
• Analysis of HDAC expression in motor neurons and skeletal muscle.
• Evaluation of muscle electrical potentials, mir206/FGFBP1 signaling, and myogenic gene expression.

Main Results:

• HDACs did not show altered expression in isolated motor neurons during ALS progression.
• Specific Class II HDACs (-4, -5, -6) expression increased in skeletal muscle of severely impaired ALS mice.
• MC1568 treatment led to early improvements in motor performance, which were not sustained.
• Motor improvement correlated with enhanced skeletal muscle electrical potentials and myogenic gene expression, not reduced motor neuron degeneration.
• MC1568 treatment reduced the activation of mir206/FGFBP1-dependent muscle reinnervation signaling.

Conclusions:

• Selective inhibition of HDAC Class II is beneficial for skeletal muscle function in ALS mice, independent of motor neuron survival.
• Targeting specific HDACs in skeletal muscle may represent a viable therapeutic strategy for ALS.
• The findings highlight the differential roles of HDACs in motor neurons versus skeletal muscle during ALS pathogenesis.