AMPK phosphorylation of FNIP1 (S220) controls mitochondrial function and muscle fuel utilization during exercise

Area of Science:

• Exercise physiology
• Mitochondrial biology
• Skeletal muscle metabolism

Background:

• Adenosine monophosphate-activated protein kinase (AMPK) activation during exercise influences skeletal muscle mitochondrial function.
• The specific effectors and regulatory pathways of AMPK in this context are not fully understood.

Purpose of the Study:

• To investigate the role of folliculin interacting protein 1 (FNIP1) phosphorylation by AMPK in regulating mitochondrial adaptation and exercise performance.
• To elucidate the molecular mechanisms linking AMPK signaling to muscle fuel utilization during physical activity.

Main Methods:

• Utilized skeletal muscle-specific transgenic mouse models expressing nonphosphorylatable (S220A) and phosphomimic (S220D) FNIP1 variants.
• Performed biochemical analyses on primary skeletal muscle cells.
• Assessed mitochondrial content, metabolic capacity, and exercise endurance in mice.

Main Results:

• Loss of FNIP1 in skeletal muscle led to increased mitochondrial content and enhanced metabolic capacity, improving exercise endurance.
• AMPK-mediated phosphorylation of FNIP1 at serine-220 (S220) was identified as a key regulator of mitochondrial electron transfer chain complex assembly and fuel utilization.
• FNIP1 phosphorylation by AMPK impacts exercise performance independently of mechanistic target of rapamycin complex 1-transcription factor EB signaling.

Conclusions:

• Folliculin interacting protein 1 (FNIP1) acts as a crucial AMPK effector in mediating mitochondrial adaptation to exercise in skeletal muscle.
• FNIP1 phosphorylation by AMPK is a key mechanism controlling muscle fuel utilization and exercise tolerance.
• This finding provides insights into exercise physiology and potential therapeutic targets for conditions affecting exercise capacity.