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Reduced muscle mass is a characteristic finding in sarcopenia, the central element of physical frailty syndrome, and a major cause of physical function decay, morbidity and mortality in the elderly. Studies so far demonstrated reduced muscle mass in depressed patients with an average age over 60 years. An open question is whether muscle mass reduction is already observed earlier. Therefore, muscle mass was assessed in middle-aged male and female depressive patients, and the findings were related to indicators of hypothalamus-pituitary adrenal axis activation, lifestyle factors, endocrine and immune measures.Sixty-seven depressed patients (mean age 38.6y; 58.2% female) and 26 healthy volunteers (mean age 40.5y; 61.5% female) were included. Muscle mass, adrenal gland volume, and intra-abdominal adipose tissue were assessed by magnetic resonance tomography. Laboratory parameters included fasting cortisol, pro-inflammatory cytokines, factors constituting the metabolic syndrome, and relative insulin resistance according to the homeostasis model assessment (HOMA-IR).We found significant effects of depression (F = 4.2; P = 0.043) and gender (F = 182; P < 0.001) on muscle mass. Muscle mass was reduced in depressed men compared to healthy men (F = 3.4; P = 0.044), particularly in those with chronic depression. In contrast, no such association was observed in depressed females. Adrenal gland volume and intra-abdominal fat was increased in depressed men and women, although not significantly. Correlations were observed for muscle mass with the amount of self-reported exercise and depression severity, and for depression severity with self-reported exercise. Further findings comprised lower self-reported activity and higher cortisol concentrations in depressed male and female compared to healthy probands.Muscle mass is reduced in middle-aged depressed men, particularly those with chronic disease course. This association is not observed in depressed females, possibly pointing to the role of female sex steroids in maintaining muscle mass. The increase of adrenal gland volume in depressed patients may point to the role of a dysregulated hypothalamus-pituitary-adrenal system. The inverse association of exercise with muscle mass demonstrates the importance of physical activity. Looking at the long term consequences of reduced muscle mass, interventions to preserve and rebuild muscle mass in depression – such as structured exercise interventions – should be recommended.Muscle mass is decreased in male patients with major depressive disorder, particular those with chronic disease course. This difference was not observed in female depressed patients. The extent of muscle mass reduction is correlated to depression severity and inversely to physical activity, pointing to the role of depression associated inactivity. Low muscle mass is a risk factor for physical frailty, therefore interventions aiming at improving physical fitness may be recommended.Sex steroids were not assessed in the study groups.Muscle mass is reduced in depressed man, particularly those with chronic disease course.Muscle mass in depression is correlated with depression severity and with physical inactivity.Given the association of depression with physical frailty of the elderly, behavioral activation and improvement of physical fitness should be recommended.