l-Carnitine: An adequate supplement for a multi-targeted anti-wasting therapy in cancer

Busquets, Sı́lvia; Serpe, Roberto; Toledo, Míriam; Betancourt, Angélica; Marmonti, Enrica; Orpí, Marcel; Pin, Fabrizio; Capdevila, Eva; Madeddu, Clelia; López‐Soriano, Francisco J.; Mantovani, Giovanni; Macciò, Antonio; Argilés, Josep Μ.

doi:10.1016/j.clnu.2012.03.005

Cited by 42 publications

(55 citation statements)

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“…For the purpose of the investigation, results obtained in the animals and those obtained in the study muscles were subsequently analyzed as follows: (1) non-exposed controls versus lung carcinogenesis mice (U group), (2) non-exposed controls versus lung emphysema-carcinogenesis mice (E–U group), and (3) U versus E–U groups of animals. The sample size chosen was based on previous studies [6–9, 11, 14, 45, 46] and on assumptions of 80 % power to detect an improvement of more than 20 % in measured outcomes at a level of significance of p ≤ 0.05. In most biological variables, mean difference between groups was initially estimated at a minimum of 20–25 % and standard deviation was approximately 25–30 % of the mean value for each of the variables.…”

Section: Methodsmentioning

confidence: 99%

Phenotypic and metabolic features of mouse diaphragm and gastrocnemius muscles in chronic lung carcinogenesis: influence of underlying emphysema

et al. 2016

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BackgroundMuscle wasting negatively impacts the progress of chronic diseases such as lung cancer (LC) and emphysema, which are in turn interrelated.ObjectivesWe hypothesized that muscle atrophy and body weight loss may develop in an experimental mouse model of lung carcinogenesis, that the profile of alterations in muscle fiber phenotype (fiber type composition and morphometry, muscle structural alterations, and nuclear apoptosis), and in muscle metabolism are similar in both respiratory and limb muscles of the tumor-bearing mice, and that the presence of underlying emphysema may influence those events.MethodsDiaphragm and gastrocnemius muscles of mice with urethane-induced lung cancer (LC-U) with and without elastase-induced emphysema (E–U) and non-exposed controls (N = 8/group) were studied: fiber type composition, morphometry, muscle abnormalities, apoptotic nuclei (immunohistochemistry), and proteolytic and autophagy markers (immunoblotting) at 20- and 35-week exposure times. In the latter cohort, structural contractile proteins, creatine kinase (CK), peroxisome proliferator-activated receptor (PPAR) expression, oxidative stress, and inflammation were also measured. Body and muscle weights were quantified (baseline, during follow-up, and sacrifice).ResultsCompared to controls, in U and E–U mice, whole body, diaphragm and gastrocnemius weights were reduced. Additionally, both in diaphragm and gastrocnemius, muscle fiber cross-sectional areas were smaller, structural abnormalities, autophagy and apoptotic nuclei were increased, while levels of actin, myosin, CK, PPARs, and antioxidants were decreased, and muscle proteolytic markers did not vary among groups.ConclusionsIn this model of lung carcinogenesis with and without emphysema, reduced body weight gain and muscle atrophy were observed in respiratory and limb muscles of mice after 20- and 35-week exposure times most likely through increased nuclear apoptosis and autophagy. Underlying emphysema induced a larger reduction in the size of slow- and fast-twitch fibers in the diaphragm of U and E–U mice probably as a result of the greater inspiratory burden imposed onto this muscle.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-1003-9) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Phenotypic and metabolic features of mouse diaphragm and gastrocnemius muscles in chronic lung carcinogenesis: influence of underlying emphysema

et al. 2016

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“…Experimental cachexia was obtained through i.p. injection of 10 8 AH‐130 Yoshida ascites hepatoma cells obtained from exponential tumours as described previously 37. The food intake was measured daily.…”

Section: Methodsmentioning

confidence: 99%

A multifactorial anti-cachectic approach for cancer cachexia in a rat model undergoing chemotherapy

Toledo

Penna

Oliva

et al. 2015

Journal of Cachexia, Sarcopenia and Muscle

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BackgroundThe effectiveness of drugs aimed at counteracting cancer cachexia is generally tested in pre‐clinical rodent models, where only the tumour‐induced alterations are taken into account, excluding the co‐presence of anti‐tumour molecules that could worsen the scenario and/or interfere with the treatment.MethodsThe aim of the present investigation has been to assess the efficacy of a multifactorial treatment, including formoterol and megestrol acetate, in cachectic tumour‐bearing rats (Yoshida AH‐130, a highly cachectic tumour) undergoing chemotherapy (sorafenib).ResultsTreatment of cachectic tumour‐bearing rats with sorafenib (90 mg/kg) causes an important decrease in tumour cell content due to both reduced cell proliferation and increased apoptosis. As a consequence, animal survival significantly improves, while cachexia occurrence persists. Multi‐factorial treatment using both formoterol and megestrol acetate is highly effective in preventing muscle wasting and has more powerful effects than the single formoterol administration. In addition, both physical activity and grip strength are significantly improved as compared with the untreated tumour‐bearing animals. The effects of the multi‐factorial treatment include increased food intake (likely due to megestrol acetate) and decreased protein degradation, as shown by the reduced expression of genes associated with both proteasome and calpain proteolytic systems.ConclusionsThe combination of the two drugs proved to be a promising strategy for treating cancer cachexia in a pre‐clinical setting that better resembles the human condition, thus providing a strong rationale for the use of such combination in clinical trials involving cachectic cancer patients.

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“…Ubiquitin-mediated proteolysis within proteasomes is the most important protein degradation pathway in tissues in general, and particularly responsible for the degradation of myofibrillar proteins in skeletal muscle which make up about 60% of total muscle proteins. Thus, the observation that carnitine supplementation reduces muscle wasting in a rat model of cancer cachexia [36], which is characterized by an increased activity of ubiquitin-mediated proteolysis, is largely explained by inhibition of this pathway. Inhibition of this pathway by carnitine supplementation is probably mediated by increasing plasma concentrations of IGF-1, which has been observed in several species including humans, pigs, rats and chickens [35, 37–41].…”

Section: Discussionmentioning

confidence: 99%

Supplemental carnitine affects the microRNA expression profile in skeletal muscle of obese Zucker rats

2014

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BackgroundIn the past, numerous studies revealed that supplementation with carnitine has multiple effects on performance characteristics and gene expression in livestock and model animals. The molecular mechanisms underlying these observations are still largely unknown. Increasing evidence suggests that microRNAs (miRNAs), a class of small non-coding RNA molecules, play an important role in post-transcriptional regulation of gene expression and thereby influencing several physiological and pathological processes. Based on these findings, the aim of the present study was to investigate the influence of carnitine supplementation on the miRNA expression profile in skeletal muscle of obese Zucker rats using miRNA microarray analysis.ResultsObese Zucker rats supplemented with carnitine had higher concentrations of total carnitine in plasma and muscle than obese control rats (P < 0.05). miRNA expression profiling in skeletal muscle revealed a subset of 152 miRNAs out of the total number of miRNAs analysed (259) were identified to be differentially regulated (adjusted P-value < 0.05) by carnitine supplementation. Compared to the obese control group, 111 miRNAs were up-regulated and 41 down-regulated by carnitine supplementation (adjusted P-value < 0.05). 14 of these miRNAs showed a log2 ratio ≥ 0.5 and 7 miRNAs showed a log2 ratio ≤ −0.5 (adjusted P-value < 0.05). After confirmation by qRT-PCR, 11 miRNAs were found to be up-regulated and 6 miRNAs were down-regulated by carnitine supplementation (P < 0.05). Furthermore, a total of 1,446 target genes within the validated miRNAs were revealed using combined three bioinformatic algorithms. Analysis of Gene Ontology (GO) categories and KEGG pathways of the predicted targets revealed that carnitine supplementation regulates miRNAs that target a large set of genes involved in protein-localization and -transport, regulation of transcription and RNA metabolic processes, as well as genes involved in several signal transduction pathways, like ubiquitin-mediated proteolysis and longterm depression, are targeted by the miRNAs regulated by carnitine supplementation.ConclusionThe present study shows for the first time that supplementation of carnitine affects a large set of miRNAs in skeletal muscle of obese Zucker rats suggesting a novel mechanism through which carnitine exerts its multiple effects on gene expression, which were observed during the past.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-512) contains supplementary material, which is available to authorized users.

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l-Carnitine: An adequate supplement for a multi-targeted anti-wasting therapy in cancer

Cited by 42 publications

References 58 publications

Phenotypic and metabolic features of mouse diaphragm and gastrocnemius muscles in chronic lung carcinogenesis: influence of underlying emphysema

Phenotypic and metabolic features of mouse diaphragm and gastrocnemius muscles in chronic lung carcinogenesis: influence of underlying emphysema

A multifactorial anti-cachectic approach for cancer cachexia in a rat model undergoing chemotherapy

Supplemental carnitine affects the microRNA expression profile in skeletal muscle of obese Zucker rats

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