Cancer cachexia decreases specific force and accelerates fatigue in limb muscle
Introduction
Cachexia is a complex metabolic syndrome associated with most advanced stage cancers that is characterized by progressive weight loss due to significant skeletal muscle wasting, with or without adipose tissue wasting [1]. The muscle wasting causes associated muscle weakness and cancer patients have shown 33–40% reductions in quadriceps muscle strength compared to healthy volunteers [2]. This weakness compromises physical function, functional independence and quality of life. Experimental models of cancer cachexia have recapitulated this limb muscle weakness, with several groups independently reporting a decrease in maximal tetanic force in the EDL and TA muscles [3], [4], [5]. These muscles are commonly studied during cancer cachexia because cachexia is known to affect glycolytic muscles to a greater extent than oxidative muscles [6], [7], [8], [9]. Interestingly, in each of these studies specific force (force normalized to cross sectional area) was not different between control and C-26 mice, suggesting that the muscle weakness is due entirely to the decrease in muscle mass. Yet recently published data from our lab [10] and another [5] clearly demonstrate a decrease in diaphragm specific force during severe cancer cachexia. These combined findings suggest heterogeneity in skeletal muscle’s response to cancer cachexia, with a decrease in the specific force of some skeletal muscles, such as the diaphragm, but not others, such as the EDL and TA muscles. This could be related to muscle use, in that the diaphragm contracts continuously whereas the EDL and TA muscles contract significantly less frequently. Therefore the aim of the current study was to determine whether severe cancer cachexia causes contractile dysfunction in the oxidative soleus muscle, a postural limb muscle that is chronically active and functionally more similar to the diaphragm. For comparative purposes we also measured contractile properties in the glycolytic EDL muscle.
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Animals
Male CD2F1 mice (∼20 g) purchased from Charles River Laboratories (Wilmington, Massachusetts) were used for all animal experiments, and all animal procedures were approved by the University of Florida Institutional Animal Care and Use Committee. Mice were provided with water and standard diet ad libitum. Mice were kept in a controlled facility on a 12 h light–dark cycle.
Cancer cachexia
Colon-26 (C-26) cells were obtained from the National Cancer Institute Tumor Repository (Frederick, MD, USA). These cells were
Results
In agreement with data recently published from our lab, C-26 mice showed a significant decrease in body weight at the study endpoint when tumor diameter reached 1.5 cm (25% decrease; data not shown). This decrease in body weight was accompanied by a significant 20% decrease in the soleus (control, 8.9 mg ± 0.4; C-26, 6.3 mg ± 0.4) and a 27% decrease in the EDL (control, 9.9 mg ± 0.3; C-26, 7.8 mg ± 0.6) muscle mass.
Discussion
The significant skeletal muscle wasting associated with cancer cachexia causes profound muscle weakness, with cancer patients showing 33–40% reductions in quadriceps muscle strength compared to healthy volunteers [2]. This magnitude of muscle weakness has substantial effects on physical function, functional independence and quality of life. To date only a handful of studies have recapitulated this muscle weakness in experimental models of cancer cachexia. Studies in the EDL and TA muscles
Acknowledgments
We thank Dr. Sarah Senf for editorial comments. This work was supported by Bankhead Coley Cancer Research Program grant 09BN-09 and U.S. National Institute of Arthritis and Musculoskeletal and Skin Diseases grant R01AR060209 (to A.R.J.) and R00HL098453 (to L.F.F.).
References (17)
- et al.
Cachexia: a new definition
Clin. Nutr.
(2008) - et al.
Oxidative phenotype protects myofibers from pathological insults induced by chronic heart failure in mice
Am. J. Pathol.
(2007) - et al.
Dystrophin glycoprotein complex dysfunction: a regulatory link between muscular dystrophy and cancer cachexia
Cancer Cell
(2005) - et al.
Morphology, metabolism, microcirculation, and strength of skeletal muscles in cancer-related cachexia
Acta Oncol.
(2009) - et al.
Mass-dependent decline of skeletal muscle function in cancer cachexia
Muscle Nerve
(2006) - et al.
Antibody-directed myostatin inhibition enhances muscle mass and function in tumor-bearing mice
Am. J. Physiol. Regul. Integr. Comp. Physiol.
(2011) - et al.
Importance of functional and metabolic impairments in the characterization of the C-26 murine model of cancer cachexia
Dis. Model. Mech.
(2012) - et al.
Inhibition of FoxO transcriptional activity prevents muscle fiber atrophy during cachexia and induces hypertrophy
FASEB J.
(2012)
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These authors contributed equally to this work.