ACVR2B/Fc counteracts chemotherapy-induced loss of muscle and bone mass

Abstract

Chemotherapy promotes the development of cachexia, a debilitating condition characterized by muscle and fat loss. ACVR2B/Fc, an inhibitor of the Activin Receptor 2B signaling, has been shown to preserve muscle mass and prolong survival in tumor hosts, and to increase bone mass in models of osteogenesis imperfecta and muscular dystrophy. We compared the effects of ACVR2B/Fc on muscle and bone mass in mice exposed to Folfiri. In addition to impairing muscle mass and function, Folfiri had severe negative effects on bone, as shown by reduced trabecular bone volume fraction (BV/TV), thickness (Tb.Th), number (Tb.N), connectivity density (Conn.Dn), and by increased separation (Tb.Sp) in trabecular bone of the femur and vertebra. ACVR2B/Fc prevented the loss of muscle mass and strength, and the loss of trabecular bone in femurs and vertebrae following Folfiri administration. Neither Folfiri nor ACVR2B/Fc had effects on femoral cortical bone, as shown by unchanged cortical bone volume fraction (Ct.BV/TV), thickness (Ct.Th) and porosity. Our results suggest that Folfiri is responsible for concomitant muscle and bone degeneration, and that ACVR2B/Fc prevents these derangements. Future studies are required to determine if the same protective effects are observed in combination with other anticancer regimens or in the presence of cancer.

Growth of ovarian cancer xenografts causes loss of muscle and bone mass: a new model for the study of cancer cachexia

“…Advanced OC patients often experience the symptoms of cachexia, an extremely debilitating condition mainly responsible for body weight loss, severe muscle and fat wasting, fatigue, decreased response to antineoplastic therapies, and overall reduced survival . We and others showed that counteraction of cachexia by means of pro‐anabolic agents prevents chemotherapy side toxicities in skeletal muscle and promotes better survival in cancer hosts, despite limited or no effects on tumour size . This also suggests that preservation of skeletal muscle mass per se may benefit quality of life and survival in patients with cancer.…”

“…Administration of ACVR2B/Fc was shown to completely restore muscle wasting in this model . ACVR2B/Fc is an inhibitor of the Activin Receptor 2B signalling known to preserve muscle mass and prolong survival in tumour hosts and to increase muscle and bone mass following chemotherapy treatment . However, based on the results of a recent genomic profiling, the TOV‐21G tumours were found to possess few copy number alterations and a ‘hyper‐mutated’ genome, thus setting this cell type apart from the rest of the OC cell lines and from the HGS‐OC tissue samples …”

“…45,46 We and others showed that counteraction of cachexia by means of proanabolic agents prevents chemotherapy side toxicities in skeletal muscle and promotes better survival in cancer hosts, despite limited or no effects on tumour size. [47][48][49]30,24 This also suggests that preservation of skeletal muscle mass per se may benefit quality of life and survival in patients with cancer. Hence, determining the mechanisms responsible for muscle wasting in OC represents a task of the utmost importance.…”

“…30 ACVR2B/Fc is an inhibitor of the Activin Receptor 2B signalling known to preserve muscle mass and prolong survival in tumour hosts and to increase muscle and bone mass following chemotherapy treatment. 48 However, based on the results of a recent genomic profiling, the TOV-21G tumours were found to possess few copy number alterations and a 'hyper-mutated' genome, thus setting this cell type apart from the rest of the OC cell lines and from the HGS-OC tissue samples. 4 In order to establish an animal model that resembles the human phenotype as close as possible, in the present study, we characterized the pro-cachectic effects associated with the in vivo growth of ES-2 OC xenografts, both at the functional and molecular level.…”

Cancer‐ and Chemotherapy‐Induced Musculoskeletal Degradation

“…Doxorubicin and carboplatin chemotherapies have been used to study musculoskeletal changes and have revealed that these agents alone cause significant reduction in bone volume . The combination therapy Folfiri (5‐fluorouracil, leucovorin, and irinotecan) also causes reduced bone volume …”