Systemic effects of tumours lead not only to CC but also to cardiac wasting, associated with LV-dysfunction, fibrotic remodelling, and increased mortality. These adverse effects of the tumour on the heart and on survival can be mitigated by treatment with either the β-blocker bisoprolol or the aldosterone antagonist spironolactone. We suggest that clinical trials employing these agents be considered to attempt to limit this devastating complication of cancer.

Background and Purpose— Muscle wasting is a common complication accompanying stroke. Although it is known to impair poststroke recovery, the mechanisms of subacute catabolism after stroke have not been investigated in detail. The aim of this study is to investigate mechanisms of local and systemic catabolism and muscle wasting (sarcopenia) in a model of ischemic stroke systematically. Methods— Changes in body composition and catabolic activation in muscle tissue were studied in a mouse model of acute cerebral ischemia (temporal occlusion of the middle cerebral artery). Tissue wasting (nuclear magnetic resonance spectroscopy), tissue catabolism (caspases-3 and -6, myostatin), and proteasome activity were assessed. Food intake, activity levels, and energy expenditure were assessed, and putative mechanisms of postischemic wasting were tested with appropriate interventions. Results— Severe weight loss in stroke animals (day 3: weight loss, –21.7%) encompassed wasting of muscle (–12%; skeletal and myocardium) and fat tissue (–27%). Catabolic signaling and proteasome activity were higher in stroke animals in the contralateral and in the ipsilateral leg. Cerebral infarct severity correlated with catabolic activity only in the contralateral leg but not in the ipsilateral leg. Lower energy expenditure in stroke animals together with normal food intake and activity levels suggests compensatory mechanisms to regain weight. Interventions (high caloric feeding, β-receptor blockade, and antibiotic treatment) failed to prevent proteolytic activation and muscle wasting. Conclusions— Catabolic pathways of muscle tissue are activated after stroke. Impaired feeding, sympathetic overactivation, or infection cannot fully explain this catabolic activation. Wasting of the target muscle of the disrupted innervation correlated to severity of brain injury. Our data indicate the presence of a stroke-specific sarcopenia.

BackgroundCachexia 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.MethodsIn 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.ResultsTreatment 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].ConclusionsMegestrol 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.

Cachexia is a common co-morbidity in cancer occurring in up to 80% of patients depending on the type of cancer. Uric acid (UA), the end-product of the purine metabolism, is elevated in cachexia due to tissue wasting and upregulated xanthine oxidase (XO) activity. High serum UA levels indicate increased XO-dependent production of oxygen free radicals (reactive oxygen species; ROS) and correlate with metabolic illness and poor survival. We hypothesized that XO-inhibition might reduce inflammatory signals accounting for tissue wasting and improve survival in experimental cancer cachexia. Animals were inoculated intraperitoneally with AH-130 hepatoma cells and treated with two XO-inhibitors: allopurinol [Allo, low (LD) and high dose (HD) 4 and 40 mg/kg/d] and its more effective active metabolite oxypurinol (Oxy, 4 and 40 mg/kg/d) or placebo for 15 days. Weight loss and tissue wasting of both fat and lean tissue (assessed by NMR-scanning) was reduced by both LD and HD Allo and LD-Oxy, but not by HDOxy. A robust induction of XO-activity for generation of reactive oxygen species was seen in the placebo group (assessed by electron paramagnetic spectroscopy), which was reduced by XO-inhibition. Increased ROS induced cytokine signaling, proteolytic activity and tissue degradation were all attenuated by XO inhibition. Survival was significantly and dose dependently improved. Food intake and spontaneous locomotor activity were higher, indicating a higher quality of life. Inhibition of XO can reduce tissue wasting and improve survival in cancer cachexia and clearly clinical studies are needed.