Zoledronic Acid Improves Muscle Function in Healthy Mice Treated with Chemotherapy

Abstract

Carboplatin is a chemotherapy drug used to treat solid tumors but also causes bone loss and muscle atrophy and weakness. Bone loss contributes to muscle weakness through bone-muscle crosstalk, which is prevented with the bisphosphonate zoledronic acid (ZA). We treated mice with carboplatin in the presence or absence of ZA to assess the impact of bone resorption on muscle. Carboplatin caused loss of body weight, muscle mass, and bone mass, and also led to muscle weakness as early as 7 days after treatment. Mice treated with carboplatin and ZA lost body weight and muscle mass but did not lose bone mass. In addition, muscle function in mice treated with ZA was similar to control animals. We also used the anti-TGFβ antibody (1D11) to prevent carboplatin-induced bone loss and showed similar results to ZA-treated mice. We found that atrogin-1 mRNA expression was increased in muscle from mice treated with carboplatin, which explained muscle atrophy. In mice treated with carboplatin for 1 or 3 days, we did not observe any bone or muscle loss, or muscle weakness. In addition, reduced caloric intake in the carboplatin treated mice did not cause loss of bone or muscle mass, or muscle weakness. Our results show that blocking carboplatin-induced bone resorption is sufficient to prevent skeletal muscle weakness and suggests another benefit to bone therapy beyond bone in patients receiving chemotherapy.n 368 HAIN ET AL. TissueMice were euthanized and the tibialis anterior (TA), soleus, and gastrocnemius were dissected. The extensor digitorum longus (EDL) muscle was dissected for muscle contractility. Muscles were either snap frozen in liquid nitrogen for biochemical analysis or embedded in optimum cutting temperature (O.C.T., Tissue Tek, Torrance, CA, USA) compound in cryomolds and frozen in liquid nitrogencooled 2-methylbutane (isopentane) for histological analysis. (38) Journal of Bone and Mineral Research ZA IMPROVES MUSCLE FUNCTION IN HEALTHY MICE TREATED WITH CHEMOTHERAPY 369 n 40. Wen Y, Murach KA, Vechetti IJ Jr, et al. MyoVision: software for automated high-content analysis of skeletal muscle immunohistochemistry. J Appl Physiol. 2018;124(1):40-51. 41. Edwards JR, Nyman JS, Lwin ST, et al. Inhibition of TGF-beta signaling by 1D11 antibody treatment increases bone mass and quality in vivo.

Formation of colorectal liver metastases induces musculoskeletal and metabolic abnormalities consistent with exacerbated cachexia

“…Though the goal of the study to examine cachexia in a context of CRC LM was achieved, future studies may consider using lower doses of C26 tumor cells or perhaps other CRC cells that may allow the progression of cachexia to extend beyond 2 weeks. Moreover, in the present study, we did not take into consideration whether the administration of chemotherapeutics further aggravate muscle wasting, especially considering that our lab and others have demonstrated that several anticancer compounds induce cachexia independently of their effects on tumor growth (24,26,27,29,30,60). Lastly, another limitation of the current study was the focus on male animals, leaving out possible sex differences in response to LMs.…”

ACVR2B antagonism as a countermeasure to multi‐organ perturbations in metastatic colorectal cancer cachexia

“…antiresorptive treatments) preserve bone and muscle mass in the presence of platinum-based chemotherapies. 70,71 Additionally, we have previously indicated that use of ACVR2B/Fc preserves muscle and bone in the presence of the commonly used chemotherapy regimen Folfiri. 22 However, to our knowledge, this is the first time that ACVR2B/Fc has shown to preserve bone and muscle together in a model of metastatic CRC.…”

“…The latter is of particular importance as we and others have demonstrated that several chemotherapies induce multi-organ cachexia independent of their effects on tumour growth. 22,23,71,[91][92][93] In this regard, targeting ACVR2B in combination with chemotherapy may prove to be a viable approach in minimizing tumour progression and the multi-organ perturbations that occur with the progression of cancer cachexia. Moreover, the present study only examined the benefits of ACVR2B/Fc on male mice bearing HCT116 LM, and as sexual dimorphism has been observed in the progression of cachexia in CRC, future studies should investigate whether ACVR2B/Fc benefits equally span across both sexes.…”

Bone metastases induce metabolic changes and mitophagy in mice

“…Protein lysates from gastrocnemius or RF muscles were prepared as previously described using NP‐40 lysis buffer (50 mM Tris pH 8.0, 150 mM NaCl, 1% NP‐40), cOmplete Mini EDTA‐free protease inhibitor tablet (MilliporeSigma, Burlington, MA, USA), phosphatase inhibitors (1 mM Na 3 OV 4 , 5 mM NaF, 1 mM phenylmethylsulfonyl fluoride) and PhosSTOP phosphatase inhibitor tablet (Sigma‐Aldrich, St Louis, MO, USA) (Hain et al., 2020). Protein concentration was determined by bicinchoninic acid assay (BCA) protein assay, Thermo Fisher, Waltham, MA, USA.…”

“…Cachexia can exist as a spectrum from muscle weakness with mild weight loss to profound muscle weakness and wasting (Fearon et al., 2011). There are no current treatments for cancer cachexia and some cancer treatments have been shown to also cause cachexia (Barreto et al., 2016; Coletti, 2018; Damrauer et al., 2018; Hain et al., 2019, 2020; Martin et al., 2015).…”