Ampk alpha2 T172 Activation Dictates Exercise Performance and Energy Transduction in Skeletal Muscle.

Area of Science:

• Biochemistry
• Molecular Biology
• Physiology

Background:

• 5'-AMP-activated protein kinase (AMPK) acts as a key sensor for metabolic regulation.
• Previous genetic studies on AMPK activation faced limitations due to protein stoichiometry disruption.

Purpose of the Study:

• To investigate the role of AMPKα2 T172 phosphorylation in skeletal muscle metabolism and function using a novel knock-in mouse model.
• To elucidate the molecular mechanisms underlying AMPK's impact on energy transduction and exercise capacity.

Main Methods:

• CRISPR/Cas9 gene editing to create Ampkα knock-in (KI) mice with a non-activatable T172A mutation.
• Phenotypic analysis of KI mice, including body composition, exercise capacity, and mitochondrial function in skeletal muscle.
• Integrated temporal multi-omic analysis (proteomics, phosphoproteomics, metabolomics) of skeletal muscle.

Main Results:

• Ampkα2 T172A KI mice exhibited increased fat-to-lean mass, reduced endurance, and impaired mitochondrial respiration in skeletal muscle.
• Multi-omic analysis revealed a critical role for Ampkα2 T172 activation in regulating glycolytic and oxidative metabolism, mitochondrial respiration, and muscle contraction.
• Skeletal muscle proteomic changes in KI mice significantly overlapped with those observed in type 2 diabetic patients.

Conclusions:

• Ampkα2 T172 activation is essential for maintaining skeletal muscle energy homeostasis and exercise performance.
• The findings highlight Ampkα2 T172 as a potential therapeutic target for metabolic disorders like type 2 diabetes.