Exercise reduces intramuscular stress and counteracts muscle weakness in mice with breast cancer

Abstract

Background Patients with breast cancer exhibit muscle weakness, which is associated with increased mortality risk and reduced quality of life. Muscle weakness is experienced even in the absence of loss of muscle mass in breast cancer patients, indicating intrinsic muscle dysfunction. Physical activity is correlated with reduced cancer mortality and disease recurrence. However, the molecular processes underlying breast cancer‐induced muscle weakness and the beneficial effect of exercise are largely unknown. Methods Eight‐week‐old breast cancer (MMTV‐PyMT, PyMT) and control (WT) mice had access to active or inactive in‐cage voluntary running wheels for 4 weeks. Mice were also subjected to a treadmill test. Muscle force was measured ex vivo. Tumour markers were determined with immunohistochemistry. Mitochondrial biogenesis and function were assessed with transcriptional analyses of PGC‐1α, the electron transport chain (ETC) and antioxidants superoxide dismutase (Sod) and catalase (Cat), combined with activity measurements of SOD, citrate synthase (CS) and β‐hydroxyacyl‐CoA‐dehydrogenase (βHAD). Serum and intramuscular stress levels were evaluated by enzymatic assays, immunoblotting, and transcriptional analyses of, for example, tumour necrosis factor‐α (TNF‐α) and p38 mitogen‐activated protein kinase (MAPK) signalling. Results PyMT mice endured shorter time and distance during the treadmill test (~30%, P < 0.05) and ex vivo force measurements revealed ~25% weaker slow‐twitch soleus muscle (P < 0.001). This was independent of cancer‐induced alteration of muscle size or fibre type. Inflammatory stressors in serum and muscle, including TNF‐α and p38 MAPK, were higher in PyMT than in WT mice (P < 0.05). Cancer‐induced decreases in ETC (P < 0.05, P < 0.01) and antioxidant gene expression were observed (P < 0.05). The exercise intervention counteracted the cancer‐induced muscle weakness and was accompanied by a less aggressive, differentiated tumour phenotype, determined by increased CK8 and reduced CK14 expression (P < 0.05). In PyMT mice, the exercise intervention led to higher CS activity (P = 0.23), enhanced β‐HAD and SOD activities (P < 0.05), and reduced levels of intramuscular stressors together with a normalization of the expression signature of TNFα‐targets and ETC genes (P < 0.05, P < 0.01). At the same time, the exercise‐induced PGC‐1α expression, and CS and β‐HAD activity was blunted in muscle from the PyMT mice as compared with WT mice, indicative that breast cancer interfere with transcriptional programming of mitochondria and that the molecular adaptation to exercise differs between healthy mice and those afflicted by disease. Conclusions Four‐week voluntary wheel running counteracted muscle weakness in PyMT mice which was accompanied by reduced intrinsic stress and improved mitochondrial and antioxidant profiles and activities that aligned with muscles of healthy mice.

Corylifol A ameliorates muscle atrophy by inhibiting TAOK1/p38‐MAPK/FoxO3 pathway in cancer cachexia

“…CYA could bind and inhibit the activation of TAOK1 in C2C12 myotubes. The involvement of p38‐MAPK pathway in cancer cachexia muscle atrophy had been reported 23,34,35 . In the present study, the p38‐MAPK pathway was observed to be activated in both TNF‐α‐treated C2C12 myotubes as well as in muscle tissues of cancer cachexia mice.…”

“…The involvement of p38-MAPK pathway in cancer cachexia muscle atrophy had been reported. 23,34,35 In the present study, the p38-MAPK pathway was observed to be activated in both TNF-α-treated C2C12 myotubes as well as in muscle tissues of cancer cachexia mice. Our results suggested that the inhibitive effects of CYA on TAOK1/p38-MAPK pathway was involved in its mechanisms of ameliorating cancer cachexia muscle atrophy.…”

Cancer Cachexia: Underlying Mechanisms and Potential Therapeutic Interventions

“…In exploring the link between inflammation and cachexia-induced muscle wasting, studies have shown that moderate-intensity endurance exercise can downregulate TNF-α, which plays pivotal roles in inflammation onset and regulation [ 288 ]. Similar results have been observed in cancerous mice, indicating the potential of aerobic exercise to decrease TNF-α expression in cachexic mice [ 289 , 290 ].…”

Passive exercise is an effective alternative to HRT for restoring OVX induced mitochondrial dysfunction in skeletal muscle

“…Reduced muscle function is linked to mitochondrial dysfunction ( 38 , 39 ). Mitochondria are critical organelles in skeletal muscle responsible for regulating its metabolic status, including chemical energy (ATP) production, regulation of intracellular Ca 2+ homeostasis, modulation of cell proliferation, and integration of apoptotic signaling ( 40 , 41 ).…”