Cancer Causes Cardiac Atrophy and Autophagy in a Sexually Dimorphic Manner

Abstract

Approximately one-third of cancer deaths are caused by cachexia, a severe form of skeletal muscle and adipose tissue wasting that affects men more than women. The heart also undergoes atrophy in cancer patients, but the mechanisms and the basis for apparent sex differences are unclear. In a mouse colon-adenocarcinoma model, cancer causes a loss of cardiac mass due to a decrease in cardiac myocyte size that is associated with reduced levels of all sarcomeric proteins. Unlike skeletal muscle cachexia, atrophic hearts do not upregulate the ubiquitin-proteasome system or its activity but increase autophagy. Thus, cancer causes cardiac atrophy by a mechanism distinct from that in skeletal muscle. Male tumor-bearing mice have a more severe phenotype than females, including greater cardiac mass loss and mortality, a more robust pro-inflammatory response to the tumor, and greater cardiac autophagy. In females, estrogen protects against cancer-induced cardiac atrophy and body weight loss by signaling through its receptor. Sex differences in cardiac atrophy need to be considered during the treatment of patients suffering from chemotherapy-induced cardiomyopathy to prevent exacerbation of cardiac dysfunction.

Establishment and characterization of a novel murine model of pancreatic cancer cachexia

“…Cardiac dysfunction is independently associated with substantial morbidity and mortality in cachexia, and its mechanistic underpinnings are therefore an important topic of investigation. Cardiac muscle catabolism in cachexia has previously been linked to induction of autophagy and variably to expression of atrophy‐associated ubiquitin ligases 46, 47. Our data establish that the KPC model is similar to other cachexia models by producing skeletal muscle catabolism by E3 ubiquitin ligase activation and cardiac muscle catabolism via autophagy, but that both pathways are active in both tissue subsets.…”

“…Importantly, the rate of muscle wasting and weight loss correspond to survival in cancer patients,70, 71 and males experience an increased degree of catabolism and an increased mortality risk in many different subsets of cancer 72, 73, 74. In the C26 model of cancer cachexia, male mice experience greater body weight loss, loss of skeletal and cardiac muscle, and mortality than tumour‐bearing females because of the protective effects of oestrogen receptor signalling 46. Our model demonstrates for the first time that LMA changes are sexually dimorphic and in females are the first behavioural signal of cachexia onset.…”

Loss of muscle mass: Current developments in cachexia and sarcopenia focused on biomarkers and treatment

“…30 Cancer cachexia animal models are showing significant wasting of the myocardium. [31][32][33] In one study it was shown that the heart muscle weight is decreased by 20% on average. 34 In another cancer cachexia study, cardiac wasting was associated with left-ventricular (LV)-dysfunction.…”

Intranasal Ginsenoside Rb1 Targets the Brain and Ameliorates Cerebral Ischemia/Reperfusion Injury in Rats

“…Interestingly, estrogen is also able to influence autophagy. 37,38) Whether GRb1 could modulate autophagy through ERrelated pathways also requires future investigation.…”