When Recovery Fails: Long COVID, Muscle Fatigue, and the Energy Cost of Survival

Why do some people never bounce back from a virus?

For millions struggling with long COVID, the answer may lie in the body’s energy economy — and how it breaks down under stress.

A new study published in Trends in Endocrinology & Metabolism by Charlton et al. (2025) sheds light on a puzzling symptom that plagues many long COVID patients: post-exertional malaise (PEM) — a crash of fatigue, pain, and cognitive fog after even mild activity. This isn’t just tiredness; it’s the body’s inability to recover from exertion.

But why?

Muscles That Can’t Bounce Back

Charlton and colleagues examined how skeletal muscle is altered in long COVID. What they found was striking:

• Mitochondria — the cell’s energy generators — are damaged and dysfunctional. These muscles can’t efficiently produce ATP, the fuel for movement and repair.

• Blood vessels show structural changes — thickened capillary walls and endothelial dysfunction — meaning oxygen and nutrients can’t easily reach muscle fibers.

• Muscle fibers shift to a more glycolytic (sugar-burning) type, which are less efficient and fatigue more quickly.

• After exercise, muscle biopsies show increased damage, inflammation, and a drop in mitochondrial function — suggesting the tissue isn’t just stressed, but crashing under the demand.

From Exercise to Exhaustion: A Bioenergetic Perspective

To understand what’s happening here, it helps to think in terms of stress adaptation and energy economics.

In any illness, the body must shift energy toward defense — immune activation, inflammation, and repair. In healthy recovery, once the threat passes, the system reallocates energy back to normal function and rebuilds capacity.

But sometimes that recovery never finishes.

In the Exposure-Related Malnutrition (ERM) model, this is seen as a failure to resolve stress adaptation. The immune system stays activated. Metabolic reserves are depleted. Mitochondria don’t bounce back. The cost of being “on alert” becomes too high.

In this state, even normal activities — like walking, thinking, or socializing — can push the system past its energy threshold, leading to crashes like PEM.

The True Cost of Survival

Charlton’s study suggests that PEM isn’t just about deconditioning or lingering inflammation. It’s a sign that the system is operating on borrowed energy — that the reserves needed to repair and recover from activity are no longer available.

This is what makes the ERM framework so powerful. It views chronic conditions like long COVID not as isolated failures, but as systemic breakdowns in energy availability and allocation:

• When energy is diverted to chronic inflammation, less is left for muscle repair.

• When oxygen delivery falters due to vascular damage, muscle metabolism suffers.

• When mitochondrial output drops, the whole body slows to conserve fuel.

Moving Forward: A Resilience-Based Approach

Understanding PEM through the ERM lens opens new possibilities:

• Diagnostics could look for early signs of energy imbalance — mitochondrial dysfunction, substrate deficits, or unresolved inflammation.

• Therapies might shift from “pushing through” activity to restoring energy availability and adaptive capacity — through nutrition, mitochondrial support, or targeted immune modulation.

• Hope lies in recognizing that what looks like weakness or laziness is often a sign of metabolic exhaustion — not moral failure.

Final Thoughts

The Charlton et al. study deepens our understanding of long COVID and PEM, but its implications stretch further. It illustrates how the body’s recovery from stress is not guaranteed — and how failure to resolve that stress can lead to a state of chronic energy debt.

In the words of the ERM framework:

“You’re not broken — you’re exhausted. You can recover. But first, we must recognize the cost of resilience.”

Charlton, B. T., Goulding, R. P., Jaspers, R. T., Appelman, B., van Vugt, M., & Wüst, R. C. I. (2025). Skeletal muscle adaptations and post-exertional malaise in long COVID. Trends in Endocrinology & Metabolism, 36(7), 614–622. https://doi.org/10.1016/j.tem.2024.11.008

#Long COVID, #Post-exertional malaise (PEM), #Mitochondrial dysfunction, #Skeletal muscle adaptation, #Bioenergetic insufficiency