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Updated: Jul 19, 2026
Models of Bone Metastasis
Published on: September 4, 2012
Excess TGF-β mediates muscle weakness associated with bone metastases in mice
David L Waning1, Khalid S Mohammad1, Steven Reiken2
1Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Abstract:
Cancer-associated muscle weakness is a poorly understood phenomenon, and there is no effective treatment. Here we find that seven different mouse models of human osteolytic bone metastases-representing breast, lung and prostate cancers, as well as multiple myeloma-exhibited impaired muscle function, implicating a role for the tumor-bone microenvironment in cancer-associated muscle weakness. We found that transforming growth factor (TGF)-β, released from the bone surface as a result of metastasis-induced bone destruction, upregulated NADPH oxidase 4 (Nox4), resulting in elevated oxidization of skeletal muscle proteins, including the ryanodine receptor and calcium (Ca(2+)) release channel (RyR1). The oxidized RyR1 channels leaked Ca(2+), resulting in lower intracellular signaling, which is required for proper muscle contraction. We found that inhibiting RyR1 leakage, TGF-β signaling, TGF-β release from bone or Nox4 activity improved muscle function in mice with MDA-MB-231 bone metastases. Humans with breast- or lung cancer-associated bone metastases also had oxidized skeletal muscle RyR1 that is not seen in normal muscle. Similarly, skeletal muscle weakness, increased Nox4 binding to RyR1 and oxidation of RyR1 were present in a mouse model of Camurati-Engelmann disease, a nonmalignant metabolic bone disorder associated with increased TGF-β activity. Thus, pathological TGF-β release from bone contributes to muscle weakness by decreasing Ca(2+)-induced muscle force production.
Insights
Cancer metastasis causes muscle weakness by releasing bone transforming growth factor-beta (TGF-β), which oxidizes skeletal muscle proteins and impairs calcium signaling. Inhibiting this pathway improved muscle function in mouse models.
Area of Science:
- Oncology
- Muscle Physiology
- Bone Biology
Background:
- Cancer-associated muscle weakness is a significant clinical problem with no effective treatments.
- The tumor-bone microenvironment's role in muscle dysfunction is poorly understood.
- Osteolytic bone metastases are common in breast, lung, prostate cancers, and multiple myeloma.
Purpose of the Study:
- To investigate the mechanisms underlying cancer-associated muscle weakness.
- To identify therapeutic targets for improving muscle function in cancer patients.
Main Methods:
- Utilized seven mouse models of human osteolytic bone metastases.
- Analyzed the effects of transforming growth factor-beta (TGF-β) on skeletal muscle proteins.
- Measured calcium (Ca2+) release and intracellular signaling in muscle fibers.
- Assessed the impact of inhibiting TGF-β signaling, Nox4 activity, and RyR1 leakage on muscle function.
Main Results:
- Metastasis-induced bone destruction released TGF-β, upregulating NADPH oxidase 4 (Nox4) in skeletal muscle.
- Nox4 caused oxidation and leakage of calcium release channel RyR1, impairing muscle contraction.
- Inhibiting RyR1 leakage, TGF-β signaling, or Nox4 activity restored muscle function in mice.
- Oxidized RyR1 was also observed in humans with bone metastases and in a mouse model of metabolic bone disease with high TGF-β activity.
Conclusions:
- Pathological TGF-β release from bone contributes to muscle weakness by disrupting calcium signaling in skeletal muscle.
- Targeting the TGF-β-Nox4-RyR1 pathway offers a potential therapeutic strategy for cancer-associated muscle weakness.
