cAMP-dependent protein kinase inhibits FoxO activity and regulates skeletal muscle plasticity in mice

Area of Science:

• Skeletal Muscle Physiology
• Molecular Biology
• Cell Signaling

Background:

• Catecholamines are known to suppress the Ubiquitin-Proteasome System (UPS) and atrophy-related gene expression in skeletal muscle via a cAMP-dependent pathway.
• However, the precise molecular mechanisms underlying this suppression remain largely unelucidated.

Purpose of the Study:

• To investigate the signaling pathways through which norepinephrine (NE) influences fasting-induced muscle atrophy.
• To determine the role of Protein Kinase A (PKA) in regulating FoxO transcription factors and skeletal muscle mass.

Main Methods:

• Administration of norepinephrine (NE) to rodents and assessment of gene expression in tibialis anterior (TA) muscles.
• Overexpression of PKA catalytic subunit (PKAcat) and its inhibitor (PKI) in muscle tissue.
• Utilizing reporter assays to measure FoxO activity and Western blotting to quantify protein levels of Atrogin-1, MuRF1, and FoxO.
• Employing dominant-negative FoxO (d.n.FoxO) to investigate its role in preventing atrophy.

Main Results:

• A single NE injection attenuated fasting-induced upregulation of FoxO-target genes by stimulating PKA/CREB and Akt/FoxO1 pathways.
• Muscle-specific PKA activation suppressed FoxO reporter activity, while PKA inhibition increased FoxO activity, Atrogin-1/MuRF1 content, and induced muscle fiber atrophy.
• Overexpression of PKAcat led to fiber-type transition towards a smaller, slower, oxidative phenotype and enhanced muscle fatigue resistance.
• The atrophy induced by PKI was preventable by d.n.FoxO expression.

Conclusions:

• Endogenous PKA activity is essential for restraining basal FoxO activity in skeletal muscle.
• PKA plays a critical physiological role in maintaining skeletal muscle mass and function.
• The findings elucidate a key molecular mechanism by which catecholamines preserve muscle homeostasis.