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

• Breast & lung
• Bone destruction

mediated by osteoclasts Osteolytic

Solid Tumor Metastases

Mouse model: human MDA-MB-231 breast cancer

100,000 cells

T

10 20 30

• 40
• 30
• 20
• 10

10

Days % change grip strength

Non-Tumor MDA-MB-231

*

50 100 150 50 150 250 350 450

Frequency (Hz) Specific Force (kN/m2)

Non-Tumor MDA-MB-231

****

Mice with MDA-MB-231 bone metastases have grip strength & muscle function

Two-way ANOVA, *p<0.05, ****p<0.0001

EDL

Waning DL. et al. (2015) Nat Medicine. 21(11):1262.; Bonetto A. et al (2015) Bonekey Rep. 4:732.

Force vs. osteolytic lesion area

é osteolysis correlates to ê muscle function and TGFb causes muscle weakness

Waning DL. et al. (2015) Nat Medicine. 21(11):1262.

TGFβ TGFb signaling in skeletal muscle: Oxidative stress (NADPH oxidase 4) Calcium leak (ryanodine receptor 1 oxidation) Contractile dysfunction

20 40 60 80 100 200 300 400 500 600

Lesion Area (mm2) Specific Force (kN/m2 at 120Hz)

***

Pearson r2 = 0.5295

Two-way ANOVA, ****p<0.0001

Grip strength EDL contractility

MDA-MB-231 + Vehicle MDA-MB-231 + ZA

50 100 150 100 200 300 400 500

Hz

Specific force (kN/m2f

****

10 20 30

• 40
• 20

20

Days % change body weight

****

MDA-MB-231 + Vehicle MDA-MB-231 + ZA

ê bone resorption with zoledronic acid restores skeletal muscle function

% change grip strength

Waning DL. et al. (2015) Nat Medicine. 21(11):1262.

Carboplatin ê tumor burden & muscle function

MDA-MB-231 vehicle carboplatin

T T

Hain BA, et al (2019) JCSM Rapid Comm. 2(1). T-test, *p<0.05 Two-way ANOVA, **p<0.01, ****p<0.0001

20 40 60 80 100

Tumor burden (% total area)

*

MDA-MB-231 + vehicle MDA-MB-231 + carboplatin

50 100 150 200 400 600

Frequency (Hz) Specific Force (kN/m2)

**** **

Non-tumor + vehicle MDA-MB-231 + vehicle Non-tumor + carboplatin MDA-MB-231 + carboplatin

50 100 150 100 200 300 400 500 600

Frequency (Hz) Specific Force (kN/m2)

Control + vehicle Carboplatin + vehicle Control + ZA Carboplatin + ZA

* **

Zoledronic acid prevents carboplatin-induced bone loss and improves muscle function

Control + vehicle Carboplatin + vehicle Control + ZA Carboplatin + ZA

Two-way ANOVA, *p<0.05, **p<0.01 Hain BA, et al (2020) J Bone Miner Res. 35(2):368.

Acknowledgements

IU School of Medicine Theresa Guise, MD Khalid Mohammad, MD PhD Brian Hain, PhD Baptiste Jude, PhD Jenna Wilcox Haifang Xu

Ph Phi Beta Ps Psi Na National Pr Project

Funding