Ubiquitin Specific Peptidase 51 Exacerbates Skeletal Muscle Injury by Enhancing APAF1-Mediated Apoptosis and...

Area of Science:

• Biochemistry
• Cell Biology
• Molecular Medicine

Background:

• Skeletal muscle injury (SMI) involves complex cellular processes like oxidative stress, inflammation, and cell death.
• The precise molecular mechanisms controlling cell death pathways in SMI are not fully understood.

Purpose of the Study:

• To identify novel molecular regulators of cell death in skeletal muscle injury.
• To investigate the role of the deubiquitinating enzyme USP51 in SMI and its underlying mechanisms.

Main Methods:

• Utilized tBHP-induced oxidative stress in C2C12 myotubes and an AAV-mediated SMI mouse model.
• Performed functional assays, bioinformatic screening, protein-protein interaction analysis, co-immunoprecipitation, and ubiquitination assays.
• Assessed cell viability, apoptosis, pyroptosis, muscle damage, myofiber integrity, and inflammation.

Main Results:

• USP51 expression was upregulated in oxidative stress models.
• USP51 knockdown enhanced cell viability and suppressed apoptosis and pyroptosis.
• USP51 directly interacted with and deubiquitinated APAF1, increasing its stability.
• USP51 deficiency alleviated SMI in mice, an effect abolished by APAF1 overexpression.

Conclusions:

• USP51 acts as a novel positive regulator of SMI by stabilizing APAF1.
• The USP51-APAF1 axis plays a critical role in amplifying muscle damage.
• Targeting the USP51-APAF1 interaction presents a potential therapeutic strategy for SMI.