Myosin heavy chain is not selectively decreased in murine cancer cachexia

Cosper, Pippa F.; Leinwand, Leslie A.

doi:10.1002/ijc.26298

Cited by 36 publications

(42 citation statements)

References 28 publications

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“…To determine whether this impairment is related to alterations in myofibrillar protein expression, we quantified MyHC and actin protein levels. Samples were processed in a high‐salt lysis buffer since a recent study clearly demonstrated their significantly greater solubility, and, therefore, more accurate quantification, when processed in this buffer (26). Normalized to total protein within the solubilized fraction, MyHC levels were decreased by 27% in the diaphragm of C‐26 mice compared to controls ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Diaphragm and ventilatory dysfunction during cancer cachexia

et al. 2013

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Cancer cachexia is characterized by a continuous loss of locomotor skeletal muscle mass, which causes profound muscle weakness. If this atrophy and weakness also occurs in diaphragm muscle, it could lead to respiratory failure, which is a major cause of death in patients with cancer. Thus, the purpose of the current study was to determine whether colon-26 (C-26) cancer cachexia causes diaphragm muscle fiber atrophy and weakness and compromises ventilation. All diaphragm muscle fiber types were significantly atrophied in C-26 mice compared to controls, and the atrophy-related genes, atrogin-1 and MuRF1, significantly increased. Maximum isometric specific force of diaphragm strips, absolute maximal calcium activated force, and maximal specific calcium-activated force of permeabilized diaphragm fibers were all significantly decreased in C-26 mice compared to controls. Further, isotonic contractile properties of the diaphragm were affected to an even greater extent than isometric function. Ventilation measurements demonstrated that C-26 mice have a significantly lower tidal volume compared to controls under basal conditions and, unlike control mice, an inability to increase breathing frequency, tidal volume, and, thus, minute ventilation in response to a respiratory challenge. These data demonstrate that C-26 cancer cachexia causes profound respiratory muscle atrophy and weakness and ventilatory dysfunction.

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Section: Resultsmentioning

confidence: 99%

Diaphragm and ventilatory dysfunction during cancer cachexia

et al. 2013

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“…This normally provides a strong mechanical link between the intracellular cytoskeleton and extracellular matrix 29. It is also thought that there is selective targeting of myofibrillar proteins, in particular MyHC, in cancer cachexia7,10 although a single study has suggested that the selective breakdown of MyHC in mice with cancer may be artefactual 30. In addition, myofibrillar degradation appears to occur in a time-dependent manner 21.…”

Section: Discussionmentioning

confidence: 99%

Evaluating potential biomarkers of cachexia and survival in skeletal muscle of upper gastrointestinal cancer patients

Stephens

Skipworth

Gallagher

et al. 2015

J cachexia sarcopenia muscle

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BackgroundIn order to grow the potential therapeutic armamentarium in the cachexia domain of supportive oncology, there is a pressing need to develop suitable biomarkers and potential drug targets. This pilot study evaluated several potential candidate biomarkers in skeletal muscle biopsies from a cohort of upper gastrointestinal cancer (UGIC) patients.MethodsOne hundred seven patients (15 weight-stable healthy controls (HC) and 92 UGIC patients) were recruited. Mean (standard deviation) weight-loss of UGIC patients was 8.1 (9.3%). Cachexia was defined as weight-loss ≥5%. Rectus abdominis muscle was obtained at surgery and was analysed by western blotting or quantitative real-time–polymerase chain reaction. Candidate markers were selected according to previous literature and included Akt and phosphorylated Akt (pAkt, n = 52), forkhead box O transcription factors (n = 59), ubiquitin E3 ligases (n = 59, control of muscle anabolism/catabolism), BNIP3 and GABARAPL1 (n = 59, as markers of autophagy), myosin heavy-chain (MyHC, n = 54), dystrophin (n = 39), β-dystroglycan (n = 52), and β-sarcoglycan (n = 52, as markers of structural alteration in a muscle). Patients were followed up for an average of 1255 days (range 581–1955 days) or until death. Patients were grouped accordingly and analysed by (i) all cancer patients vs. HC; (ii) cachectic vs. non-cachectic cancer patients; and (iii) cancer patients surviving ≤1 vs. >1 year post operatively.ResultsCancer compared with HC patients had reduced mean (standard deviation) total Akt protein [0.49 (0.31) vs. 0.89 (0.17), P = 0.001], increased ratio of phosphorylated to total Akt [1.33 (1.04) vs. 0.32 (0.21), P = 0.002] and increased expression of GABARAPL1 [1.60 (0.76) vs. 1.10 (0.57), P = 0.024]. β-Dystroglycan levels were higher in cachectic compared with non-cachectic cancer patients [1.01 (0.16) vs. 0.87 (0.20), P = 0.007]. Survival was shortened in patients with low compared with high MyHC levels (median 316 vs. 1326 days, P = 0.023) and dystrophin levels (median 341 vs. 660 days, P = 0.008).ConclusionsThe present study has identified intramuscular protein level of β-dystroglycan as a potential biomarker of cancer cachexia. Changes in the structural elements of muscle (MyHC or dystrophin) appear to be survival biomarkers.

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“…For optimal extraction and processing of MHC and actin, muscles were homogenized in a high-salt lysis buffer as described previously (Cosper and Leinwand, 2012;Roberts et al, 2013b). Samples were mixed in Laemmli buffer (Bio-Rad, Hercules, CA) and heated.…”

Section: Contractile Protein Analysesmentioning

confidence: 99%

HDAC1 activates FoxO and is both sufficient and required for skeletal muscle atrophy

Beharry

Sandesara

Roberts

et al. 2014

Journal of Cell Science

103

116

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The Forkhead box O (FoxO) transcription factors are activated, and necessary for the muscle atrophy, in several pathophysiological conditions, including muscle disuse and cancer cachexia. However, the mechanisms that lead to FoxO activation are not well defined. Recent data from our laboratory and others indicate that the activity of FoxO is repressed under basal conditions via reversible lysine acetylation, which becomes compromised during catabolic conditions. Therefore, we aimed to determine how histone deacetylase (HDAC) proteins contribute to activation of FoxO and induction of the muscle atrophy program. Through the use of various pharmacological inhibitors to block HDAC activity, we demonstrate that class I HDACs are key regulators of FoxO and the muscle-atrophy program during both nutrient deprivation and skeletal muscle disuse. Furthermore, we demonstrate, through the use of wild-type and dominant-negative HDAC1 expression plasmids, that HDAC1 is sufficient to activate FoxO and induce muscle fiber atrophy in vivo and is necessary for the atrophy of muscle fibers that is associated with muscle disuse. The ability of HDAC1 to cause muscle atrophy required its deacetylase activity and was linked to the induction of several atrophy genes by HDAC1, including atrogin-1, which required deacetylation of FoxO3a. Moreover, pharmacological inhibition of class I HDACs during muscle disuse, using MS-275, significantly attenuated both disuse muscle fiber atrophy and contractile dysfunction. Together, these data solidify the importance of class I HDACs in the muscle atrophy program and indicate that class I HDAC inhibitors are feasible countermeasures to impede muscle atrophy and weakness.

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Myosin heavy chain is not selectively decreased in murine cancer cachexia

Cited by 36 publications

References 28 publications

Diaphragm and ventilatory dysfunction during cancer cachexia

Diaphragm and ventilatory dysfunction during cancer cachexia

Evaluating potential biomarkers of cachexia and survival in skeletal muscle of upper gastrointestinal cancer patients

HDAC1 activates FoxO and is both sufficient and required for skeletal muscle atrophy

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