Comprehensive Proteomics and β-Hydroxybutyrylation Profiling in Starvation-Induced Gastrocnemius Muscle Remodeling.

Area of Science:

• Muscle metabolism research
• Post-translational modification
• Nutrient deprivation adaptations

Background:

• Skeletal muscle undergoes significant metabolic changes during starvation.
• Lysine β-hydroxybutyrylation (Kbhb) is a metabolite-derived modification linked to ketone metabolism.
• The role of Kbhb in muscle adaptation to starvation is largely unknown.

Purpose of the Study:

• To investigate the role of lysine β-hydroxybutyrylation (Kbhb) in skeletal muscle during starvation.
• To characterize global proteomic and Kbhb changes in gastrocnemius muscle following food deprivation.
• To understand how Kbhb modifies protein function in response to energy deficiency.

Main Methods:

• Mice were subjected to 72 hours of food deprivation.
• Integrative quantitative proteomics was performed on gastrocnemius muscle.
• Kbhb-modified peptides were profiled to identify modified sites and proteins.

Main Results:

• Starvation led to body weight and muscle mass loss, increased systemic β-hydroxybutyrate, and widespread Kbhb modifications.
• Proteomics revealed downregulation of ribosomal proteins and upregulation of autophagy and lipid catabolism pathways.
• Over 7500 Kbhb sites were identified, with increased modification on metabolic enzymes and decreased modification on structural proteins.

Conclusions:

• Lysine β-hydroxybutyrylation is a dynamic, metabolically responsive post-translational modification in skeletal muscle during fasting.
• Kbhb plays a regulatory role in modulating enzymatic activity of key metabolic pathways.
• These findings expand the understanding of metabolite-driven regulatory mechanisms in muscle metabolism.