Bone-muscle crosstalk: cancer- and chemotherapy- induced muscle - PowerPoint PPT Presentation

Bone-muscle crosstalk: cancer- and chemotherapy- induced muscle weakness David Waning, PhD Associate Professor of Cellular & Molecular Physiology Penn State University

Solid Tumor Metastases Osteolytic • Breast & lung • Bone destruction mediated by osteoclasts Mouse model: human MDA-MB-231 breast cancer 100,000 cells T

Mice with MDA-MB-231 bone metastases have grip strength & muscle function Days % change grip strength 10 10 20 30 0 Non-Tumor -10 MDA-MB-231 -20 * -30 -40 450 Specific Force (kN/m 2 ) 350 250 **** EDL 150 Non-Tumor MDA-MB-231 50 0 50 100 150 Frequency (Hz) Two-way ANOVA, *p<0.05, ****p<0.0001 Waning DL. et al. (2015) Nat Medicine. 21(11):1262.; Bonetto A. et al (2015) Bonekey Rep . 4:732.

é osteolysis correlates to ê muscle function and TGF b causes muscle weakness Force vs. osteolytic lesion area 600 (kN/m 2 at 120Hz) Specific Force 500 400 300 *** Pearson r 2 = 0.5295 200 0 20 40 60 80 100 Waning DL. et al. (2015) Lesion Area (mm 2 ) Nat Medicine. 21(11):1262. TGF b signaling in skeletal muscle: TGFβ Oxidative stress (NADPH oxidase 4) Calcium leak (ryanodine receptor 1 oxidation) Contractile dysfunction

ê bone resorption with zoledronic acid restores skeletal muscle function Grip strength EDL contractility 500 20 % change body weight % change grip strength Specific force (kN/m 2 f **** 400 0 300 10 20 30 **** 200 -20 MDA-MB-231 + Vehicle 100 MDA-MB-231 + ZA 0 -40 0 50 100 150 Days MDA-MB-231 + Vehicle Hz MDA-MB-231 + ZA Two-way ANOVA, ****p<0.0001 Waning DL. et al. (2015) Nat Medicine. 21(11):1262.

Carboplatin ê tumor burden & muscle function MDA-MB-231 Specific Force (kN/m 2 ) 600 MDA-MB-231 + vehicle **** vehicle MDA-MB-231 + carboplatin T Tumor burden (% total area) ** 400 100 80 Non-tumor + vehicle 200 * 60 MDA-MB-231 + vehicle Non-tumor + carboplatin 40 carboplatin MDA-MB-231 + carboplatin 20 0 0 50 100 150 0 T Frequency (Hz) Two-way ANOVA, **p<0.01, ****p<0.0001 T-test, *p<0.05 Hain BA, et al (2019) JCSM Rapid Comm. 2(1).

Zoledronic acid prevents carboplatin-induced bone loss and improves muscle function Control + vehicle Control + ZA Carboplatin + ZA Carboplatin + vehicle 600 ** Specific Force (kN/m 2 ) * 500 400 Control + vehicle 300 Carboplatin + vehicle 200 Control + ZA Carboplatin + ZA 100 0 50 100 150 Hain BA, et al (2020) Frequency (Hz) Two-way ANOVA, *p<0.05, **p<0.01 J Bone Miner Res. 35(2):368.

Acknowledgements Brian Hain, PhD Baptiste Jude, PhD Jenna Wilcox Haifang Xu IU School of Medicine Theresa Guise, MD Khalid Mohammad, MD PhD Funding Ph Phi Beta Ps Psi Na National Pr Project