To Örebro University

Introduction: Patients with breast cancer experience muscle dysfunction, which is a clinical challenge that is not restricted to advanced stage patients, but also observed in newly diagnosed weight-stable patients with low tumor burden. Recent data indicate that physical activity can reduce breast cancerassociated mortality, suggesting that improved muscle performance per secan have positive impact on survival. Here, the transgenic PyMT mouse model of breast cancer was used to elucidate molecular mechanisms underlying breast cancer-induced muscle impairments.

Materials and Methods: PyMT mice and wildtype (WT) littermates w/wo access to an in-cage running wheel for four weeks (week 8-12). Functional readouts included Ca2+imaging; isometric force measurement on single fibers and intact fast-and slow-twitchmuscles. Intramuscular signaling was assessed using immunofluorescence, immunoblotting and enzymatic assays.

Results: The specific force (i.e. force/cross-sectional area) was significantly decreased by ~ 35% in slow-twitch soleus muscles from breast cancermice as compared to WT muscles, which was the result of reduced Ca2+release and impaired myofibrillar function. There were no difference in muscle size or fiber type between the two groups. However, higher intramuscular stress (e.g. p38 activation and carbonylation (DNP)) was observed in PyMT than in WT. Intriguingly, voluntary running for four weeks reversed the weakness and PyMT soleus muscles generated similar forces as muscles of exercised WT mice. The running induced higher SOD2 expression and normalized levels of p38 and DNP.

Conclusion: Intrinsic contractile dysfunction and higher intramuscular stress was present in mice with breast cancer, which was counteracted with voluntary running.