Background Cachexia is a complex metabolic syndrome associated with cancer.
One of the features of cachexia is the loss of muscle mass, characterized by
an imbalance between protein synthesis and protein degradation. Muscle atrophy
is caused by the hyperactivation of some of the main cellular catabolic
pathways, including autophagy. Cachexia also affects the cardiac muscle. As a
consequence of the atrophy of the heart, cardiac function is impaired and
mortality is increased. Anti-cachectic therapy in patients with cancer
cachexia is so far limited to nutritional support and anabolic steroids. The
use of the appetite stimulant megestrol acetate (MA) has been discussed as a
treatment for cachexia. Methods In this study the effects of MA were tested in
cachectic tumour-bearing rats (Yoshida AH-130 ascites hepatoma). Rats were
treated daily with 100 mg/kg of MA or placebo starting one day after tumour
inoculation, and for a period of 16 days. Body weight and body composition
were assessed at baseline and at the end of the study. Cardiac function was
analysed by echocardiography at baseline and at day 11. Locomotor activity and
food intake were assessed before tumour inoculation and at day 11. Autophagic
markers were assessed in gastrocnemius muscle and heart by western blot
analysis. Results Treatment with 100 mg/kg/day MA significantly attenuated the
loss of body weight (−9 ± 12%, P < 0.05) and the wasting of lean and fat mass
(−7.0 ± 6% and −22.4 ± 3 %, P < 0.001 and P < 0.05, respectively).
Administration of 100 mg/kg/day MA significantly protected the heart from
general atrophy (633.8 ± 30 mg vs. placebo 474 ± 13 mg, P < 0.001). Tumour-
bearing rats displayed cardiac dysfunction, as indicated by the significant
impairment of the left ventricular ejection fraction, the left ventricular
fractional shortening, the stroke volume, the end dyastolic volume, and the
end systolic volume. In contrast, MA significantly improved left ventricular
ejection fraction, left ventricular fractional shortening, and left
ventricular end systolic volume. Western blotting analysis showed an
upregulation of the autophagic pathway in the gastrocnemius and hearts of the
placebo-treated tumour-bearing rats. Treatment with MA, however, was able to
modulate the autophagic markers (e.g. Beclin-1, p62, TRAF6, and LC3) in the
gastrocnemius and in the hearts of tumour-bearing rats. Most importantly, 100
mg/kg/day MA reduced mortality [hazard ratio (HR): 0.44; 95%CI: 0.20–1.00; P =
0.0486]. Conclusions Megestrol acetate improved survival and reduced wasting
through a marked downregulation of autophagy, occurring in both skeletal and
heart muscle, the latter effect leading to a significant improvement of
cardiac function. Our data suggest that MA might represent a valuable strategy
to counteract the development of cancer cachexia-induced cardiomyopathy