Exercise-A Panacea of Metabolic Dysregulation in Cancer: Physiological and Molecular Insights

Abstract

Metabolic dysfunction is a comorbidity of many types of cancers. Disruption of glucose metabolism is of concern, as it is associated with higher cancer recurrence rates and reduced survival. Current evidence suggests many health benefits from exercise during and after cancer treatment, yet only a limited number of studies have addressed the effect of exercise on cancer-associated disruption of metabolism. In this review, we draw on studies in cells, rodents, and humans to describe the metabolic dysfunctions observed in cancer and the tissues involved. We discuss how the known effects of acute exercise and exercise training observed in healthy subjects could have a positive outcome on mechanisms in people with cancer, namely: insulin resistance, hyperlipidemia, mitochondrial dysfunction, inflammation, and cachexia. Finally, we compile the current limited knowledge of how exercise corrects metabolic control in cancer and identify unanswered questions for future research.

Keywords: adipose tissue; cancer; cancer cachexia; exercise; insulin resistance; metabolism; skeletal muscle.

Figure 1

Cancer is often associated with reduced insulin sensitivity, hyperlipidemia, impaired mitochondrial function, chronic inflammation, as well as lowered muscle mass and strength (cancer cachexia). Exercise powerfully improves all of these conditions in healthy humans, suggesting that exercise could be a strategy to counter metabolic derangements in cancer.

Figure 2

Cancer is associated with adverse changes of metabolic important tissues, including skeletal muscle (myocytes), adipose tissue (adipocytes), and the liver (hepatocytes). Those changes include insulin resistance, hyperlipidemia, mitochondria dysfunction, inflammation, and muscle mass loss (cancer cachexia) and there is significant tissue crosstalk. Abbreviations: ATGL; adipose triglyceride lipase, HSL; hormone sensitive lipase, ROS; reactive oxygen species.

Figure 3

Illustration of the temporal metabolic benefits of exercise and molecular mechanisms. (A) One exercise bout elicits an acute and transient increase in muscle glucose uptake that is independent of insulin and persists in insulin-resistant subjects. (B) Insulin sensitivity (illustrated here as insulin-stimulated glucose uptake) is transiently enhanced for up to 48 h after the last exercise bout. (C) Repeated exercise training leads to longer-term adaptations, including increased expression of fat- and glucose-handling proteins and increased capillarization that improves insulin sensitivity and elevates muscle fat- and glucose-handling capacity. Abbreviations: AMP-activated protein kinase, FA; fatty acid, RAC1; Ras-related C3 botulinum toxin substrate 1, ROS, reactive oxygen species, TBC1D1; TBC1 Domain Family Member 1.