Anorexia nervosa (AN), a disorder principally of female adolescents, is characterized by prolonged self-imposed restriction of food intake leading to significant weight loss and an emaciated appearance, the result not only of loss of fat tissue but also of muscle tissue. The body responds to the caloric restriction with adaptive metabolic and physiological responses not different from those found in starvation [1
]. Many adjustments, such as hypothermia, hypotension, bradycardia, and a low resting metabolic rate, are aimed at preserving energy [2
]. Despite high rates of dieting among teenagers, the incidence of AN remains low [3
]. The apparent ease with which previously healthy teenagers lose up to 40% of their body weight poses the question whether other factors besides a restricted caloric intake might facilitate weight loss in AN.
A recent genetic study [4
] nested AN within the correlational structure of compulsive psychiatric disorders, pointing to motion as a marker. Actually, the earliest clinical descriptions refer to the persistence of movement in cachectic AN patients. In Lasègue’s words: “another ascertained fact is, that so far from muscular power being diminished, this abstinence tends to increase the aptitude for movement” [5
]. Janet [6
] writes: “It is the exaggerated need for physical movement which accompanies true anorexia nervosa”. The contemporary fitness culture tends to explain high activity levels in emaciated AN patients as a willful strategy to increase caloric expenditure. From a physiological point of view, however, hyperactivity [7
], excessive exercise [8
], and even spontaneous daily activity levels not different from normal [9
] under extreme fasting conditions appear incompatible with “the muscular power being diminished”. The increased urge for movement and restlessness [10
] and normal spontaneous physical activity levels in emaciated AN patients appear to be generated by neurophysiological and/or metabolic changes during starvation and suggest an anomaly in the biobehavioral regulation of the adaptation to starvation in AN [12
]. The underlying mechanisms are not known, except for the contribution of low leptin plasma levels [13
]. To our knowledge, the hypothesis that specific starvation-induced adaptations in the skeletal musculature of AN patients might create conditions that promote restlessness and persistent mobility has not been examined.
This review comparing studies in healthy humans, fasting or on restricted diets, with studies in AN patients, found similar adjustments to prolonged undernutrition in skeletal muscle morphology and muscle function in both groups. Furthermore, taking into account the reductions in strength and work capacity that characterized both groups, the reviewed studies provide no evidence for specific starvation-induced adaptations in muscle distinctive for AN which could shed light on the increased urge for movement and the preserved spontaneous activity in AN patients. The comparison does, however, highlight the unusual nature of the persistent restless activity in AN (see Table 1
). The findings ought to be considered preliminary, serving as a stepping stone towards future research for investigating changes in muscle tissue in AN at the cellular and genetic level, and the pathways integrating motor, cognitive and emotional input at the motor cortex. The way in which the two groups experienced the reduction in muscle tissue and the decline in functional performance differed. Participants in the starvation experiments reported subjective physical and psychological signs (i.e., tiredness, muscle soreness, weakness, avoidance of activity), all characteristic of severe undernutrition. In contrast, studies in AN did not report subjective signs of weakness or debility; several referred to continued physical activity in patients. It is of interest that once adolescent AN patients were questioned, they did report fatigue and having no energy along with an increased urge for movement and motor restlessness, although they had not volunteered this information [10
Overall, the experimental studies in healthy male subjects and the investigations in AN patients show that prolonged, severely calorie-deficient food intake resulting in significant body weight loss is associated with loss of muscle tissue and a decline in muscle strength and function. Adaptive changes in muscle tissue and function appear to be largely a function of the caloric deficit, with the duration of undernutrition playing a lesser role. AN patients were found to have widely varying deficient caloric intake, yet their tendency to eat some food seems to have prevented severe deterioration of muscle function until patients became dangerously cachectic.
Loss of muscle mass was significant and proportionately greater in male participants of the Minnesota experiments than in female AN patients, likely due to constitutional differences, although the overall younger age of AN patients may have contributed to preserving muscle tissue.
Concerning the ability to function on a daily basis, a moderate reduction in muscle tissue in the Carnegie experiments did not impair daily activities, albeit the men complained of leg weakness and greater effort. By contrast, at double the weight loss, the men in the Minnesota experiments experienced a significant decline both in grip strength and endurance. With work capacity and running time markedly reduced (by about 70%), many men felt debilitated by the end of the study.
In a similar way, when tested, physical performance in AN patients was found to be compromised, showing a reduction to 30–49% of the work capacity in healthy controls. The younger the patients’ age, the shorter the duration of illness, the less severe the weight loss, and the better the performance. The energy content of muscle seems to be of fundamental importance for physical performance in conjunction with metabolic factors, such as the ketogenic milieu [65
], since as early as eight days after high caloric re-feeding, physical performance in AN patients was shown to improve before there were detectable changes in lean body mass [58
]. AN patients typically continue to engage fully in daily activities and attend school until they are hospitalized, even when weight loss exceeds 40%.
Electrophysiological function tests of muscle strength and endurance in undernourished individuals and in AN patients showed an abnormal contractility pattern in the adductor pollicis muscle at low frequencies. This abnormal force of contraction at the lowest frequency was already recorded after five days of total fasting in healthy women and appears to be an adaptive physiological response once a critical negative metabolic balance is reached. Re-feeding completely reversed the electrophysiological changes. Muscle fatiguability was increased after two weeks of fasting, as well as in AN patients. The findings that voluntary activation of the femoris muscle was one third of normal at a mean weight loss of 42%, whereas it was comparable to healthy women at a lesser 29% weight loss, suggests that AN patients seem to be able to retain resistance capacities in leg muscles during endurance exercise, despite being considerably underweight.
Histochemical studies of the quadriceps femoris muscle in AN patients and a study in obese patients on a restricted diet concurred in finding significant muscle fiber atrophy, not only of type I fibers, albeit type II fibers were most severely affected. No signs of muscle degeneration were observed. Motor and sensory nerve conduction velocities tended to be normal, with the exception of the most cachectic AN patients, whose motor nerve conduction was slower than in controls.
Few investigators have examined muscle metabolism during undernutrition in humans. The reduced plasma carnosinase activities in patients with AN, likely due to metabolic changes in muscle and other tissues, may function to sustain normal serum carnosine levels during undernutrition [55
]. A diminished lactate response to ischemic exercise in the forearm muscle in AN patients, which suggests the possibility of a localized defect in an aerobic glycolysis in AN, was observed only by McLoughlin et al. [52
]. This finding, in conjunction with the abnormally high glycogen accumulation in muscle fibers under light microscopy [31
], deserves further investigation. On the other hand, in another study, total muscle glycogen content was reduced by 50% in AN patients when analyzed spectrophotometrically and normalized with re-feeding [54
The absence of differences in the starvation-induced adjustments in muscle between undernourished healthy individuals and AN patients can serve as an impetus for expanding the search to the cellular level, for instance to identify intramyocellular signals sensitive to nutrient availability. Since genetic factors have a significant influence on the development of AN [67
], comparisons of the gene expression profile in skeletal muscle in undernourished healthy individuals and AN patients might provide new information.
We must keep in mind that the integrity of muscle, controlled by the primary motor cortex, is not the only factor determining mobility. A comparison between undernourished healthy individuals and AN patients found that perceptions of fatigue or effort are important aspects for the experience of movement. Intriguingly, two symptoms typical of AN (mental alertness and neglect of the starved body) suggest an involvement of central nervous system structures.
Therefore, a better understanding of the central nervous system neural circuitry mediating alertness and directing motor control of spontaneous activity and the sense of motor urgency might provide more information about the mechanisms underlying the persistent restless activity in AN patients.