Systemic blockade of ACVR2B ligands prevents chemotherapy-induced muscle wasting by restoring muscle protein synthesis without affecting oxidative capacity or atrogenes

Abstract

Doxorubicin is a widely used and effective chemotherapy drug. However, cardiac and skeletal muscle toxicity of doxorubicin limits its use. Inhibiting myostatin/activin signalling can prevent muscle atrophy, but its effects in chemotherapy-induced muscle wasting are unknown. In the present study we investigated the effects of doxorubicin administration alone or combined with activin receptor ligand pathway blockade by soluble activin receptor IIB (sACVR2B-Fc). Doxorubicin administration decreased body mass, muscle size and bone mineral density/content in mice. However, these effects were prevented by sACVR2B-Fc administration. Unlike in many other wasting situations, doxorubicin induced muscle atrophy without markedly increasing typical atrogenes or protein degradation pathways. Instead, doxorubicin decreased muscle protein synthesis which was completely restored by sACVR2B-Fc. Doxorubicin administration also resulted in impaired running performance without effects on skeletal muscle mitochondrial capacity/function or capillary density. Running performance and mitochondrial function were unaltered by sACVR2B-Fc administration. Tumour experiment using Lewis lung carcinoma cells demonstrated that sACVR2B-Fc decreased the cachectic effects of chemotherapy without affecting tumour growth. These results demonstrate that blocking ACVR2B signalling may be a promising strategy to counteract chemotherapy-induced muscle wasting without damage to skeletal muscle oxidative capacity or cancer treatment.

Treating cachexia using soluble ACVR2B improves survival, alters mTOR localization, and attenuates liver and spleen responses

“…Colon 26 carcinoma (C26) cells (provided by Dr Fabio Penna, obtained from Prof. Mario P. Colombo and originally characterized by Corbett et al) were maintained in complete Dulbecco's Modified Eagle's Medium (high glucose, GlutaMAX™ Supplement, pyruvate, Gibco™, Life Technologies) supplemented with penicillin (100 U/mL), streptomycin (100 μg/mL), and 10% FBS. Our pilot experiments showed that injecting mice with C26 cells (5 × 10 5 ), resulted in marked cachexia and considerably higher tumour gene expression of Activin A , Interleukin ‐ 6 ( Il ‐ 6 ) and Myostatin in comparison to our previously conducted experiment using the LLC tumour model ( Online Resource 1: Figure S1) with the same number of cells injected (5 × 10 5 ), but larger tumour (data not shown).…”

“…Muscle protein synthesis was analysed using surface sensing of translation method as earlier in our laboratory . Briefly, on Day 11 after C26 cell inoculation, mice were anaesthetized and subsequently injected i.p.…”

“…Western blot analysis was performed as previously described . Briefly, tissue homogenates containing 30 μg of protein were solubilized in Laemmli sample buffer and heated at 95°C (except at 50°C for the analysis of OXPHOS proteins) to denature proteins, separated by SDS‐PAGE and then transferred to PVDF membrane followed by overnight probing with primary antibodies at +4°C.…”

“…Myostatin and activins negatively regulate muscle mass through binding to their receptors activin receptor type 2 (ACVR2) A and B . Blocking these ligands or their receptors can increase muscle mass and prevent muscle wasting in various animal models, but also in humans …”

Treatment with soluble activin type IIB-receptor improves bone mass and strength in a mouse model of Duchenne muscular dystrophy

“…The use of a soluble activin type IIA-receptor has been shown to increase bone mass in several in vivo [5, 6, 8] models. The effects of soluble activin type IIB-receptor (ActRIIB-Fc) on bone metabolism have also been studied recently [9–12]. Furthermore, exercise, in addition to its various other health benefits, may have positive effects on bones of young individuals [13, 14].…”