Classical NF-κB activation impairs skeletal muscle oxidative phenotype by reducing IKK-α expression

Area of Science:

• Muscle physiology
• Cellular signaling
• Pulmonary disease research

Background:

• Chronic obstructive pulmonary disease (COPD) is linked to quadriceps muscle oxidative phenotype (OXPHEN) loss.
• The classical NF-κB pathway's role in inflammation-induced muscle OXPHEN impairment is known, but mechanisms are unclear.
• IκB kinase α (IKK-α), a regulator of the alternative NF-κB pathway, is a novel positive regulator of skeletal muscle OXPHEN.

Purpose of the Study:

• To investigate if inflammation-induced classical NF-κB activation contributes to muscle OXPHEN loss in COPD by reducing IKK-α expression.
• To explore the role of IKK-α in maintaining muscle OXPHEN.
• To examine the impact of modulating the alternative NF-κB pathway on muscle OXPHEN.

Main Methods:

• Classical NF-κB signaling was activated in cultured myotubes to assess its impact on muscle OXPHEN and IKK-α levels.
• The alternative NF-κB pathway was modulated in the presence and absence of inflammatory stimuli.
• Quadriceps muscle biopsies from COPD patients and controls were analyzed for IKK-α, OXPHEN markers, and TNF-α expression.

Main Results:

• IKK-α knockdown decreased OXPHEN markers and regulators in myotubes.
• Classical NF-κB activation reduced IKK-α levels, and IKK-α overexpression prevented TNF-α-induced OXPHEN impairment.
• COPD patients showed reduced muscle IKK-α and OXPHEN compared to controls, particularly those with higher TNF-α levels.

Conclusions:

• Classical NF-κB activation impairs skeletal muscle OXPHEN by decreasing IKK-α expression.
• Reduced muscle IKK-α due to TNF-α may accelerate OXPHEN deterioration in COPD.
• Targeting IKK-α could be a therapeutic strategy for COPD-related muscle dysfunction.