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

Mader, Theresa (författare)
Karolinska Institutet
Chaillou, Thomas, 1985- (författare)
Örebro universitet,Institutionen för hälsovetenskaper,Department of Physiology and Pharmacology, Molecular Muscle Physiology and Pathophysiology, Karolinska Institutet, Biomedicum, Stockholm, Sweden,Karolinska Inst, Dept Physiol & Pharmacol Mol Muscle Physiol & Pat, Solnavagen 9, SE-17177 Stockholm, Sweden.;Örebro Univ, Sch Hlth Sci, Örebro, Sweden.
Alves, Estela Santos (författare)
Department of Physiology and Pharmacology, Molecular Muscle Physiology and Pathophysiology, Karolinska Institutet, Biomedicum, Stockholm, Sweden,Karolinska Inst, Dept Physiol & Pharmacol Mol Muscle Physiol & Pat, Solnavagen 9, SE-17177 Stockholm, Sweden.
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Jude, Baptiste (författare)
Karolinska Institutet
Cheng, Arthur J. (författare)
Department of Physiology and Pharmacology, Molecular Muscle Physiology and Pathophysiology, Karolinska Institutet, Biomedicum, Stockholm, Sweden; Muscle Health Research Centre, School of Kinesiology and Health Science, Faculty of Health Toronto, York University, Toronto, Ontario, Canada,Karolinska Inst, Dept Physiol & Pharmacol Mol Muscle Physiol & Pat, Solnavagen 9, SE-17177 Stockholm, Sweden.;York Univ, Muscle Hlth Res Ctr, Sch Kinesiol & Hlth Sci, Fac Hlth Toronto, Toronto, ON, Canada.
Kenne, Ellinor (författare)
Karolinska Institutet
Mijwel, Sara (författare)
Karolinska Institutet
Kurzejamska, Ewa (författare)
Uppsala universitet,Institutionen för immunologi, genetik och patologi
Vincent, Clara Theresa (författare)
Uppsala universitet,Institutionen för immunologi, genetik och patologi,NYU, Dept Microbiol, Grossman Sch Med, New York, NY 10016 USA.
Rundqvist, Helene (författare)
Karolinska Institutet
Lanner, Johanna T. (författare)
Karolinska Institutet
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 (creator_code:org_t)
2022-02-15
2022
Engelska.
Ingår i: Journal of Cachexia, Sarcopenia and Muscle. - : John Wiley & Sons. - 2190-5991 .- 2190-6009. ; 13:2, s. 1151-1163
  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
Stäng  
  • 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Fysiologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Physiology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

Nyckelord

Breast cancer
Mitochondria
Muscle weakness
Stress

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