Many factors in the surrounding environment have been reported to influence erythrocyte deformability. It is likely that some influences represent reversible changes in erythrocyte rigidity that may be involved in physiological regulation, while others represent the early stages of eryptosis, i.e., the red cell self-programmed death. For example, erythrocyte rigidification during exercise is probably a reversible physiological mechanism, while the alterations of red blood cells (RBCs) observed in pathological conditions (inflammation, type 2 diabetes, and sickle-cell disease) are more likely to lead to eryptosis. The splenic clearance of rigid erythrocytes is the major regulator of RBC deformability. The physicochemical characteristics of the surrounding environment (thermal injury, pH, osmolality, oxidative stress, and plasma protein profile) also play a major role. However, there are many other factors that influence RBC deformability and eryptosis. In this comprehensive review, we discuss the various elements and circulating molecules that might influence RBCs and modify their deformability: purinergic signaling, gasotransmitters such as nitric oxide (NO), divalent cations (magnesium, zinc, and Fe++), lactate, ketone bodies, blood lipids, and several circulating hormones. Meal composition (caloric and carbohydrate intake) also modifies RBC deformability. Therefore, RBC deformability appears to be under the influence of many factors. This suggests that several homeostatic regulatory loops adapt the red cell rigidity to the physiological conditions in order to cope with the need for oxygen or fuel delivery to tissues. Furthermore, many conditions appear to irreversibly damage red cells, resulting in their destruction and removal from the blood. These two categories of modifications to erythrocyte deformability should thus be differentiated.

Recent literature shows that exercise is not simply a way to generate a calorie deficit as an add-on to restrictive diets but exerts powerful additional biological effects via its impact on mitochondrial function, the release of chemical messengers induced by muscular activity, and its ability to reverse epigenetic alterations. This review aims to summarize the current literature dealing with the hypothesis that some of these effects of exercise unexplained by an energy deficit are related to the balance of substrates used as fuel by the exercising muscle. This balance of substrates can be measured with reliable techniques, which provide information about metabolic disturbances associated with sedentarity and obesity, as well as adaptations of fuel metabolism in trained individuals. The exercise intensity that elicits maximal oxidation of lipids, termed LIPOXmax, FATOXmax, or FATmax, provides a marker of the mitochondrial ability to oxidize fatty acids and predicts how much fat will be oxidized over 45–60 min of low- to moderate-intensity training performed at the corresponding intensity. LIPOXmax is a reproducible parameter that can be modified by many physiological and lifestyle influences (exercise, diet, gender, age, hormones such as catecholamines, and the growth hormone-Insulin-like growth factor I axis). Individuals told to select an exercise intensity to maintain for 45 min or more spontaneously select a level close to this intensity. There is increasing evidence that training targeted at this level is efficient for reducing fat mass, sparing muscle mass, increasing the ability to oxidize lipids during exercise, lowering blood pressure and low-grade inflammation, improving insulin secretion and insulin sensitivity, reducing blood glucose and HbA1c in type 2 diabetes, and decreasing the circulating cholesterol level. Training protocols based on this concept are easy to implement and accept in very sedentary patients and have shown an unexpected efficacy over the long term. They also represent a useful add-on to bariatric surgery in order to maintain and improve its weight-lowering effect. Additional studies are required to confirm and more precisely analyze the determinants of LIPOXmax and the long-term effects of training at this level on body composition, metabolism, and health.