IBMS BoneKEy | BoneKEy Watch

Waning et al. Bone factors implicated in cancer-related muscle wasting

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DOI:10.1038/bonekey.2016.13

Waning et al. studied murine models of metastatic bone cancer arising from seven different human cancers, showing that muscle weakness was very common, suggesting that muscle weakness associated with cancer could be linked with activity in the tumor-bone microenvironment.

Further analysis revealed that bone destruction induced by metastasis led to the release of transforming growth factor (TGF)-β, from the bone surface. This upregulated NADPH oxidase 4 (Nox4) and caused enhanced oxidization of skeletal muscle proteins, including the calcium release channel (RyR1) and the receptor for ryanodine. The resulting leakage of calcium ions from the oxidized RyR1 channels reduced intracellular signaling, causing impaired muscle contraction.

Confirmation of the role of (TGF)-β came from two sources. Firstly, human patients with bone metastases due to lung cancer or breast cancer also showed oxidized RyR1 in their skeletal muscle (control patients did not). Secondly, the same changes were noted in mice bred to model Camurati-Engelmann disease, a nonmalignant metabolic bone disorder in which TGF-β activity is greatly increased.

Interestingly, inhibition of calcium ion leakage from RyR1 or blocking TGF-β signalling or its release from bone or obstructing Nox4 activity led to improved muscle function in the affected mice.

Editor’s comment: This study provides novel mechanistic insights into the causes of cancer-associated muscle dysfunction, opening a new avenue for treatments to improve muscle weakness.

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