Blocking ActRIIB and restoring appetite reverses cachexia and improves survival in mice with lung cancer

Abstract

Cancer cachexia is a common, debilitating condition with limited therapeutic options. Using an established mouse model of lung cancer, we find that cachexia is characterized by reduced food intake, spontaneous activity, and energy expenditure accompanied by muscle metabolic dysfunction and atrophy. We identify Activin A as a purported driver of cachexia and treat with ActRIIB-Fc, a decoy ligand for TGF-β/activin family members, together with anamorelin (Ana), a ghrelin receptor agonist, to reverse muscle dysfunction and anorexia, respectively. Ana effectively increases food intake but only the combination of drugs increases lean mass, restores spontaneous activity, and improves overall survival. These beneficial effects are limited to female mice and are dependent on ovarian function. In agreement, high expression of Activin A in human lung adenocarcinoma correlates with unfavorable prognosis only in female patients, despite similar expression levels in both sexes. This study suggests that multimodal, sex-specific, therapies are needed to reverse cachexia.

Impaired Barrier Integrity of the Skeletal Muscle Vascular Endothelium Drives Progression of Cancer Cachexia

“…We hypothesized that circulating factors released by the tumor could affect the remote muscle vasculature because muscle capillary vessels respond to factors in the blood. Activin, a member of the transforming growth factor beta (TGFβ) superfamily which regulates cell differentiation, is elevated in the blood in multiple chronic diseases 41–44 . Activin-A has been reported to suppress EC proliferation under hypoxia 45 suggesting the possibility that Activin-A acts as a negative regulator of muscle vasculature.…”

“…Activin, a member of the transforming growth factor beta (TGFβ) superfamily which regulates cell differentiation, is elevated in the blood in multiple chronic diseases [41][42][43][44] . Activin-A has been reported to suppress EC proliferation under hypoxia 45 suggesting the possibility that Activin-A acts as a negative regulator of muscle vasculature.…”

Exogenous detection of 13C-glucose metabolism in tumor and diet-induced obesity models

“…TB mice displayed a similar AEE during the dark/active phase and comparable REE during the light/resting cycle compared to WT despite the presence of lung tumors ( Figure 2F ). However, skeletal muscle is the main tissue contributing to TEE ( Tschöp et al, 2011 ; Goncalves et al, 2018 ; Queiroz et al, 2022 ) and TB mice exhibited decreased lean mass and locomotor activity ( Figures 2D,E ). Taken together, these data suggest that the decreased supply of dietary energy is compensated by a reduction in energy consumed for movement as AEE and REE were similar between both genotypes.…”

“…We did not observe differences in activity or resting energy expenditure despite the presence of lung tumors. However, skeletal muscle is a primary determinant of TEE ( Speakman, 2013 ; Goncalves et al, 2018 ; Queiroz et al, 2022 ) and TB mice exhibited decreased lean mass and locomotor activity. In contrast, early-onset obese mice did not display changes in lean mass or locomotor activity but exhibited increased body weight and fat mass.…”

Impaired Barrier Integrity of the Skeletal Muscle Vascular Endothelium Drives Progression of Cancer Cachexia

“…We hypothesized that circulating factors released by the tumor could affect the remote muscle vasculature becausemuscle capillary vessels respond to factors in the blood. Activin, a member of the transforming growth factor beta (TGFβ) superfamily which regulates cell differentiation, is elevated in the blood in multiple chronic diseases [41][42][43][44] .…”