Muscle weakness and
cachexia are significant
paraneoplastic syndromes of many advanced
cancers. Osteolytic bone
metastases are common in advanced
breast cancer and are a major contributor to decreased survival, performance, and quality of life for patients.
Pathologic fracture caused by osteolytic
cancer in bone (OCIB) leads to a significant (32%) increased risk of death compared to patients without fracture. Since
muscle weakness is linked to risk of falls which are a major cause of fracture, we have investigated skeletal muscle response to OCIB. Here, we show that a syngeneic mouse model of OCIB (4T1 mammary
tumor cells) leads to
cachexia and skeletal muscle weakness associated with oxidation of the
ryanodine receptor and
calcium (Ca2+) release channel (
RyR1).
Muscle atrophy follows known pathways via both
myostatin signaling and expression of muscle-specific
ubiquitin ligases, atrogin-1 and MuRF1. We have identified a mechanism for skeletal muscle weakness due to increased oxidative stress on
RyR1 via NAPDH
oxidases [NADPH oxidase 2 (Nox2) and
NADPH oxidase 4 (Nox4)]. In addition, SMAD3 phosphorylation is higher in muscle from
tumor-bearing mice, a critical step in the intracellular signaling pathway that transmits TGFβ signaling to the nucleus. This is the first time that skeletal muscle weakness has been described in a syngeneic model of OCIB and represents a unique model system in which to study
cachexia and changes in skeletal muscle.