Cancer cachexia decreases specific force and accelerates fatigue in limb muscle

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Highlights

  • C-26 cancer cachexia causes a significant decrease in limb muscle absolute force.

  • C-26 cancer cachexia causes a significant decrease in limb muscle specific force.

  • C-26 cancer cachexia decreases fatigue resistance in the soleus muscle.

  • C-26 cancer cachexia prolongs time to peak twitch tension in limb muscle.

  • C-26 cancer cachexia prolongs one half twitch relaxation time in limb muscle.

Abstract

Cancer cachexia is a complex metabolic syndrome that is characterized by the loss of skeletal muscle mass and weakness, which compromises physical function, reduces quality of life, and ultimately can lead to mortality. Experimental models of cancer cachexia have recapitulated this skeletal muscle atrophy and consequent decline in muscle force generating capacity. However, more recently, we provided evidence that during severe cancer cachexia muscle weakness in the diaphragm muscle cannot be entirely accounted for by the muscle atrophy. This indicates that muscle weakness is not just a consequence of muscle atrophy but that there is also significant contractile dysfunction. The current study aimed to determine whether contractile dysfunction is also present in limb muscles during severe Colon-26 (C26) carcinoma cachexia by studying the glycolytic extensor digitorum longus (EDL) muscle and the oxidative soleus muscle, which has an activity pattern that more closely resembles the diaphragm. Severe C-26 cancer cachexia caused significant muscle fiber atrophy and a reduction in maximum absolute force in both the EDL and soleus muscles. However, normalization to muscle cross sectional area further demonstrated a 13% decrease in maximum isometric specific force in the EDL and an even greater decrease (17%) in maximum isometric specific force in the soleus. Time to peak tension and half relaxation time were also significantly slowed in both the EDL and the solei from C-26 mice compared to controls. Since, in addition to postural control, the oxidative soleus is also important for normal locomotion, we further performed a fatigue trial in the soleus and found that the decrease in relative force was greater and more rapid in solei from C-26 mice compared to controls. These data demonstrate that severe cancer cachexia causes profound muscle weakness that is not entirely explained by the muscle atrophy. In addition, cancer cachexia decreases the fatigue resistance of the soleus muscle, a postural muscle typically resistant to fatigue. Thus, specifically targeting contractile dysfunction represents an additional means to counter muscle weakness in cancer cachexia, in addition to targeting the prevention of muscle atrophy.

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.

Section snippets

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.).

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These authors contributed equally to this work.

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