TGFβ Regulates Bone Metastasis–Associated Skeletal Muscle Weakness

Patients with advanced cancer often develop bone metastases, which secrete factors that induce osteoclastic bone resorption and lead to the release of bone matrix growth factors, including TGFβ, which promote tumor growth and osteolysis. Bone metastases are also often associated with debilitating skeletal muscle weakness, for which there is no effective treatment. Research has focused on increasing muscle mass in patients, but it is unclear whether increased muscle mass is sufficient to improve muscle function. Waning, Mohammad, and colleagues showed that TGFβ activity mediates metastasis-related skeletal muscle weakness using mouse models of advanced human cancers that are often associated with bone metastases and muscle weakness, including breast, prostate, and lung cancers and multiple myeloma. Mice with osteolytic bone metastases exhibited decreased muscle function and increased oxidation of skeletal muscle proteins, in particular the ryanodine receptor 1 (RYR1) calcium (Ca²⁺) release channel. RYR1 oxidation was also detected in humans with cancer-associated bone metastases and resulted in pathologic leaking of Ca²⁺ from the sarcoplasmic reticulum, which contributes to muscle weakness. In contrast, mice with mammary tumors without bone metastases had normal muscle function and no Ca²⁺ leakage from RYR1 channels. Further, preventing RYR1 Ca²⁺ release with the channel stabilizer Rycal (S107) improved muscle strength without affecting muscle mass, indicating that loss of muscle mass does not fully explain the muscle weakness associated with bone metastases. Likewise, TGFβ inhibition enhanced muscle strength, whereas TGFβ treatment was sufficient to trigger RYR1 channel remodeling and intracellular Ca²⁺ leakage via induction of NADPH oxidase 4 (NOX4) and increased interaction of NOX4 with RYR1, leading to RYR1 oxidation. These findings suggest that cancer-associated skeletal muscle weakness is induced by osteolysis and the resulting increase in TGFβ activity in the tumor-bone microenvironment. Targeting TGFβ (or its release from bone by blocking bone destruction), NOX4, or RYR1 might help to alleviate skeletal muscle weakness in patients with bone metastases.

Waning DL, Mohammad KS, Reiken S, Xie W, Andersson DC, John S, et al. Excess TGFβ mediates muscle weakness associated with bone metastases in mice. Nat Med 2015;21:1262–71.

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