RYR1 and breast carcinoma: Indeed, reduced contractile protein expression or function may also contribute to weakness in bone metastases and could be involved in the novel link we described between bone destruction and weakness via the TGFβ‐Nox4‐RyR1 axis.121 Mice with breast cancer bone metastases also exhibit severe cachexia in addition to TGFβ‐mediated Ca2+ mishandling, after initial muscle weakness is detected.121 Other factors released from the bone matrix during osteolytic bone destruction, such as activin, may contribute to muscle atrophy that is independent of RyR1 Ca2+ leak and remains to be investigated.