The High Costs of Low-Grade Inflammation: Persistent Fatigue as a Consequence of Reduced Cellular-Energy Availability and Non-adaptive Energy Expenditure

Abstract

Chronic or persistent fatigue is a common, debilitating symptom of several diseases. Persistent fatigue has been associated with low-grade inflammation in several models of fatigue, including cancer-related fatigue and chronic fatigue syndrome. However, it is unclear how low-grade inflammation leads to the experience of fatigue. We here propose a model of an imbalance in energy availability and energy expenditure as a consequence of low-grade inflammation. In this narrative review, we discuss how chronic low-grade inflammation can lead to reduced cellular-energy availability. Low-grade inflammation induces a metabolic switch from energy-efficient oxidative phosphorylation to fast-acting, but less efficient, aerobic glycolytic energy production; increases reactive oxygen species; and reduces insulin sensitivity. These effects result in reduced glucose availability and, thereby, reduced cellular energy. In addition, emerging evidence suggests that chronic low-grade inflammation is associated with increased willingness to exert effort under specific circumstances. Circadian-rhythm changes and sleep disturbances might mediate the effects of inflammation on cellular-energy availability and non-adaptive energy expenditure. In the second part of the review, we present evidence for these metabolic pathways in models of persistent fatigue, focusing on chronic fatigue syndrome and cancer-related fatigue. Most evidence for reduced cellular-energy availability in relation to fatigue comes from studies on chronic fatigue syndrome. While the mechanistic evidence from the cancer-related fatigue literature is still limited, the sparse results point to reduced cellular-energy availability as well. There is also mounting evidence that behavioral-energy expenditure exceeds the reduced cellular-energy availability in patients with persistent fatigue. This suggests that an inability to adjust energy expenditure to available resources might be one mechanism underlying persistent fatigue.

Nutritional Status as a Mediator of Fatigue and Its Underlying Mechanisms in Older People

“…Additionally, it is well documented that micronutrient deficiencies may determine oxidative stress and consequently, feed a vicious circle with inflammation. Chronic low-grade inflammation has also been implicated in mediating a wide range of chronic conditions characterized by the presence of fatigue [43].…”

“…Interestingly, acetyl L-carnitine administration has been reported to reduce both mental and physical fatigue in older people [126] and vitamin D deficiency has been associated with both mental and physical fatigue [101]. Given that fatigue often has been suggested to be due to inflammation and oxidative stress, antioxidant supplementation has been proposed as a strategy to reduce fatigue [43]. Nicotinamide adenine dinucleotide and coenzyme Q10 has been reported to reduce fatigue in CFS patients [127,128].…”

“…Nicotinamide adenine dinucleotide and coenzyme Q10 has been reported to reduce fatigue in CFS patients [127,128]. Additionally, in animal models, it has been documented that antioxidants can lead to a reduction of fatigue [43]. However, the evidence in humans is still sparse [129].…”

Acceptance & Commitment Therapy for ME/CFS (Chronic Fatigue Syndrome) – A feasibility study

“…However, there is evident merit in investigating peripheral aspects of sickness behavior as they are more easily accessible, for example by investigating inflammatory marker levels in blood and subjective experiences. The relationship between cytokine-mediated inflammation and the development of fatigue and neurocognitive symptoms have been explored in for example cancer-related fatigue (73)(74)(75). Although preliminary, the results from such studies indicate an association between the variation of inflammatory markers and the development of longstanding fatigue and cognitive dysfunction.…”

Supporting Relaxation: Slowbreath for People With Myalgic Encephalomyelitis

“…While struggling with these fluctuating symptoms and health issues, self-management strategies seem to be, at present, the best option. Energy balancing (Lacourt et al, 2018) is one commonly used self-management strategy which involves balancing periods of rest and activity to avoid overexertion (Goudsmit et al, 2012).…”