Discerning primary and secondary factors responsible for clinical fatigue in multisystem diseases

Abstract

Fatigue is a common symptom of numerous acute and chronic diseases, including myalgic encephalomyelitis/chronic fatigue syndrome, multiple sclerosis, heart failure, cancer, and many others. In these multi-system diseases the physiological determinants of enhanced fatigue encompass a combination of metabolic, neurological, and myofibrillar adaptations. Previous research studies have focused on adaptations specific to skeletal muscle and their role in fatigue. However, most have neglected the contribution of physical inactivity in assessing disease syndromes, which, through deconditioning, likely contributes to symptomatic fatigue. In this commentary, we briefly review disease-related muscle phenotypes in the context of whether they relate to the primary disease or whether they develop secondary to reduced physical activity. Knowledge of the etiology of the skeletal muscle adaptations in these conditions and their contribution to fatigue symptoms is important for understanding the utility of exercise rehabilitation as an intervention to alleviate the physiological precipitants of fatigue.

Figure 1

Physiological function (represented here as a composite index of muscle size, strength, and oxidative capacity, relative to maximum) declines with age (green hatched line), to which declines from disease (magenta hatched line) and muscle deconditioning (blue hatched line) produce a cumulative phenotype. The rates of decline in this figure are hypothetical and do not represent actual data. The primary disease effect is simply what the disease would present in the absence of muscle deconditioning. Exercise rehabilitation may partially or fully correct the effect of muscle deconditioning, except in the case of ME/CFS, where standard therapeutic approaches involving exercise may in fact exacerbate the condition. In general, it is not clear whether exercise therapy can also blunt or reverse aspects of the age-related decline in physiological function. While the sensation of fatigue tracks muscle physiological function, the magnitude of the sensation (relative to the maximum experienced) may be proportionally greater than the proportionate loss of physiological function.