Excess TGF-β mediates muscle weakness associated with bone metastases in mice

Abstract

Cancer-associated muscle weakness is poorly understood 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 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/calcium (Ca2+) release channel (RyR1). The oxidized RyR1 channels leaked Ca2+, resulting in lower intracellular signaling required for proper muscle contraction. We found that inhibiting RyR1 leak, TGF-β signaling, TGF-β release from bone or Nox4 all improved muscle function in mice with MDA-MB-231 bone metastases. Humans with breast cancer- or lung cancer-associated bone metastases also had oxidized skeletal muscle RyR1 that is not seen in normal muscle. Similarly, skeletal muscle weakness, higher levels of Nox4 protein and Nox4 binding to RyR1, and oxidation of RyR1 were present in a mouse model of Camurati-Engelmann disease, a non-malignant metabolic bone disorder associated with increased TGF-β activity. Thus, metastasis-induced TGF-β release from bone contributes to muscle weakness by decreasing Ca2+-induced muscle force production.

Mechanisms of metabolic dysfunction in cancer-associated cachexia

“…Notably, mice with skeletal muscle expression of Pgc1α4 were protected from CAC (Ruas et al 2012). As an additional mechanism for skeletal muscle dysfunction in cancer, TGFβ release from bone metastasis has been demonstrated to lower intracellular calcium signaling and reduce the force of muscle contraction (Waning et al 2015).…”

The pathogenesis and treatment of cardiac atrophy in cancer cachexia

“…Myostatin, a ligand of the transforming growth factor-␤ (TGF-␤ superfamily of proteins) has also been implicated as the expression of myostatin, and one of its downstream signaling proteins p-Smad3 were increased in the cachectic hearts of AH-130 tumor-bearing rats (86,101). Furthermore, TGF-␤ released from bone due to metastasis-induced bone destruction was recently shown to cause significant skeletal muscle weakness (115). This was due, at least in part, to enhanced oxidization of the ryanodine receptor-1 causing an increase in sarcoplasmic reticulum Ca 2ϩ leak and a subsequent reduction in intracellular signaling required for muscle contraction (115).…”

“…Furthermore, TGF-␤ released from bone due to metastasis-induced bone destruction was recently shown to cause significant skeletal muscle weakness (115). This was due, at least in part, to enhanced oxidization of the ryanodine receptor-1 causing an increase in sarcoplasmic reticulum Ca 2ϩ leak and a subsequent reduction in intracellular signaling required for muscle contraction (115). Whether a similar mechanism occurs in cardiac muscle atrophy associated with bone metastasis is not known, but TGF-␤1 has been shown to regulate ryanodine receptor-mediated sarcoplasmic reticulum Ca 2ϩ oscillations in cardiac myocytes (78).…”

Bone mineral density and content are differentially impacted by aerobic and resistance training in the colon-26 mouse model of cancer cachexia

“…Given that several signaling events are common to both muscle and bone, inter-organ cross-talk and concurrent degeneration of bone in cancer cachexia is not surprising [8][9][10]. It was recently reported that metastasized bone contributes to cachexia-associated skeletal muscle dysfunction [11], suggesting regulation of skeletal muscle by bone. Furthermore, targeted treatment of cachexia via antibodies improved both lean body mass and bone mineral density [12].…”