Endurance Exercise: IL-1’s Role in Muscle Adaptations

Introduction

A Japanese study using genetically modified mice has identified a surprising new mechanism for how endurance exercise builds better muscle. The research, led by Ayumi Naito at Sapporo Medical University, shows that the inflammatory signaling molecule interleukin-1 (IL-1), once thought only to respond to injury, is essential for driving key metabolic adaptations.

Interleukin-1 Signals Muscle to Adapt, Not Just to Repair

Interleukin-1 is best known for its role in injury and infection, promoting inflammation to clear debris and start healing. Naito’s team, however, focused on its role in repeated, non-damaging exercise. They compared normal wild-type mice with mice genetically engineered to lack both IL-1α and IL-1β (IL-1 KO). After five weeks of endurance training via electrical muscle stimulation, the results were stark. Only the normal mice showed improved muscle endurance, increased mitochondrial respiration, and higher activity of citrate synthase, a marker of mitochondrial content.

The trained muscles in normal mice also produced more PGC-1α, the central coordinator of mitochondrial biogenesis, and increased proteins in the mitochondrial respiratory chain. Mice lacking IL-1 saw none of these benefits. A single exercise session increased IL-1β mRNA in normal mice, confirming that exercise itself triggers this signal. “Our findings suggest that IL-1 signaling is associated with endurance training-induced improvements in muscle endurance and mitochondrial quantity and quality,” the authors conclude.

How a Cytokine Switch Turns On the PGC-1α Engine

The study provides a clear molecular pathway linking exercise stress to long-term adaptation. The process starts when muscle contraction and metabolic stress prompt an initial release of IL-1β. This cytokine then activates the p38 MAPK enzyme. Phosphorylated, active p38 MAPK acts as a direct on-switch for the PGC-1α gene.

Increased PGC-1α protein sets off a cascade of changes: it instructs the cell to create more mitochondria (biogenesis) and upgrades the quality of existing ones. It also increases hexokinase 2, an enzyme that helps muscle cells take up and use glucose. The researchers confirmed this chain by showing that the exercise-induced phosphorylation of p38 MAPK and the subsequent rise in PGC-1α and hexokinase 2 mRNA were significantly weaker in the IL-1 knockout mice. This pathway explains how a transient inflammatory signal can translate into lasting metabolic fitness.

This mechanism is distinct from the AMPK pathway often activated by higher-intensity exercise or energy stress, as noted in a related 2026 review on metabolic disease. Both p38 MAPK/PGC-1α and AMPK are complementary systems the body uses to improve metabolic health through different exercise stimuli.

From Mouse Muscle to Human Metabolic Fitness

This research shifts the perspective on exercise-induced inflammation. Low levels of signaling molecules like IL-1 are not necessarily detrimental; they are a fundamental part of the body’s communication system to initiate positive change. This supports the rationale behind Zone 2 or other steady-state endurance training, where repeated, manageable physiological stress generates adaptive signals without causing significant muscle damage that requires long repair.

The findings also intersect with broader themes of metabolic health. PGC-1α’s role in enhancing mitochondrial function is a key defense against insulin resistance and metabolic dysfunction. By clarifying how endurance exercise reliably boosts PGC-1α, this research underscores why regular aerobic activity is a cornerstone for managing conditions like metabolic syndrome. While the study uses an animal model, the p38 MAPK/PGC-1α pathway is highly conserved and active in human skeletal muscle.

Applying the IL-1/PGC-1α Research to Your Training

For endurance athletes and fitness enthusiasts, this science reinforces several practical principles. First, consistency is paramount. The adaptive process described requires repeated stimulation; the mice trained three times per week for five weeks. Regular, moderate sessions that elevate IL-1 signaling without excessive damage are effective for building mitochondrial capacity.

Second, it highlights the importance of recovery. While IL-1 is necessary for adaptation, it is part of a tightly regulated system. Allowing the signaling cycle to complete and reset is crucial. This means balancing training with adequate rest, nutrition, and sleep, strategies also supported by research into how the gut microbiome aids recovery.

Finally, it adds a molecular explanation for the benefits of polarized training models, where a large volume of low-intensity exercise (like Zone 2) provides the chronic stimulus for this IL-1/PGC-1α pathway, while smaller doses of high-intensity work stimulate other pathways like AMPK. This balanced approach can maximize overall metabolic adaptation.

Frequently Asked Questions

Does this mean inflammation from exercise is good?

Yes, in a specific, controlled way. The study shows that the cytokine IL-1β, released during non-damaging endurance exercise, acts as a necessary signal to turn on genes for mitochondrial growth and improved metabolism, redefining it as a constructive part of the adaptation process.

Should I train if I’m sore or feeling inflamed?

It depends on the type of inflammation. Severe muscle damage and soreness (DOMS) require recovery. However, the mild, systemic inflammation following a moderate endurance session may be part of this adaptive signaling. Listening to your body and prioritizing low-intensity activity during recovery periods is advised.

Can supplements boost the PGC-1α pathway?

While certain compounds like resveratrol have been studied for activating PGC-1α in lab settings, the most potent and reliable way to increase skeletal muscle PGC-1α is through consistent endurance exercise, which naturally engages the IL-1/p38 MAPK pathway described in this research.

How does this relate to Zone 2 training specifically?

Zone 2 training provides the repeated, sustainable metabolic stress that likely triggers this beneficial IL-1 signaling without the mechanical damage of higher intensities. This makes it an efficient method for chronically stimulating the PGC-1α pathway to build mitochondrial density and improve metabolic efficiency.

Sources:
https://pubmed.ncbi.nlm.nih.gov/42572021/
https://pubmed.ncbi.nlm.nih.gov/42568389/
https://pubmed.ncbi.nlm.nih.gov/42505346/