L-carnitine ameliorates the muscle wasting of cancer cachexia through the AKT/FOXO3a/MaFbx axis

Abstract Background Recent studies suggest potential benefits of applying L-carnitine in the treatment of cancer cachexia, but the precise mechanisms underlying these benefits remain unknown. This study was conducted to determine the mechanism by which L-carnitine reduces cancer cachexia. Methods C2...

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Autores principales:	Changpeng Wu, Mingxing Zhu, Zongliang Lu, Yaowen Zhang, Long Li, Na Li, Liangyu Yin, He Wang, Wei Song, Hongxia Xu
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Cancer cachexia Muscle atrophy L-carnitine Colon-26 C2C12 cells AKT Nutrition. Foods and food supply TX341-641 Nutritional diseases. Deficiency diseases RC620-627
Acceso en línea:	https://doaj.org/article/2d96e81ea85d4a71b0776218586d425c
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spelling	oai:doaj.org-article:2d96e81ea85d4a71b0776218586d425c2021-11-08T10:44:29ZL-carnitine ameliorates the muscle wasting of cancer cachexia through the AKT/FOXO3a/MaFbx axis10.1186/s12986-021-00623-71743-7075https://doaj.org/article/2d96e81ea85d4a71b0776218586d425c2021-11-01T00:00:00Zhttps://doi.org/10.1186/s12986-021-00623-7https://doaj.org/toc/1743-7075Abstract Background Recent studies suggest potential benefits of applying L-carnitine in the treatment of cancer cachexia, but the precise mechanisms underlying these benefits remain unknown. This study was conducted to determine the mechanism by which L-carnitine reduces cancer cachexia. Methods C2C12 cells were differentiated into myotubes by growing them in DMEM for 24 h (hrs) and then changing the media to DMEM supplemented with 2% horse serum. Differentiated myotubes were treated for 2 h with TNF-α to establish a muscle atrophy cell model. After treated with L-carnitine, protein expression of MuRF1, MaFbx, FOXO3, p-FOXO3a, Akt, p-Akt, p70S6K and p-p70S6K was determined by Western blotting. Then siRNA-Akt was used to determine that L-carnitine ameliorated cancer cachexia via the Akt/FOXO3/MaFbx. In vivo, the cancer cachexia model was established by subcutaneously transplanting CT26 cells into the left flanks of the BALB/c nude mice. After treated with L-carnitine, serum levels of IL-1, IL-6 and TNF-α, and the skeletal muscle content of MuRF1, MaFbx, FOXO3, p-FOXO3a, Akt, p-Akt, p70S6K and p-p70S6K were measured. Results L-carnitine increased the gastrocnemius muscle (GM) weight in the CT26-bearing cachexia mouse model and the cross-sectional fiber area of the GM and myotube diameters of C2C12 cells treated with TNF-α. Additionally, L-carnitine reduced the protein expression of MuRF1, MaFbx and FOXO3a, and increased the p-FOXO3a level in vivo and in vitro. Inhibition of Akt, upstream of FOXO3a, reversed the effects of L-carnitine on the FOXO3a/MaFbx pathway and myotube diameters, without affecting FOXO3a/MuRF-1. In addition to regulating the ubiquitination of muscle proteins, L-carnitine also increased the levels of p-p70S6K and p70S6K, which are involved in protein synthesis. Akt inhibition did not reverse the effects of L-carnitine on p70S6K and p-p70S6K. Hence, L-carnitine ameliorated cancer cachexia via the Akt/FOXO3/MaFbx and p70S6K pathways. Moreover, L-carnitine reduced the serum levels of IL-1 and IL-6, factors known to induce cancer cachexia. However, there were minimal effects on TNF-α, another inducer of cachexia, in the in vivo model. Conclusion These results revealed a novel mechanism by which L-carnitine protects muscle cells and reduces inflammation related to cancer cachexia.Changpeng WuMingxing ZhuZongliang LuYaowen ZhangLong LiNa LiLiangyu YinHe WangWei SongHongxia XuBMCarticleCancer cachexiaMuscle atrophyL-carnitineColon-26C2C12 cellsAKTNutrition. Foods and food supplyTX341-641Nutritional diseases. Deficiency diseasesRC620-627ENNutrition & Metabolism, Vol 18, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Cancer cachexia Muscle atrophy L-carnitine Colon-26 C2C12 cells AKT Nutrition. Foods and food supply TX341-641 Nutritional diseases. Deficiency diseases RC620-627
spellingShingle	Cancer cachexia Muscle atrophy L-carnitine Colon-26 C2C12 cells AKT Nutrition. Foods and food supply TX341-641 Nutritional diseases. Deficiency diseases RC620-627 Changpeng Wu Mingxing Zhu Zongliang Lu Yaowen Zhang Long Li Na Li Liangyu Yin He Wang Wei Song Hongxia Xu L-carnitine ameliorates the muscle wasting of cancer cachexia through the AKT/FOXO3a/MaFbx axis
description	Abstract Background Recent studies suggest potential benefits of applying L-carnitine in the treatment of cancer cachexia, but the precise mechanisms underlying these benefits remain unknown. This study was conducted to determine the mechanism by which L-carnitine reduces cancer cachexia. Methods C2C12 cells were differentiated into myotubes by growing them in DMEM for 24 h (hrs) and then changing the media to DMEM supplemented with 2% horse serum. Differentiated myotubes were treated for 2 h with TNF-α to establish a muscle atrophy cell model. After treated with L-carnitine, protein expression of MuRF1, MaFbx, FOXO3, p-FOXO3a, Akt, p-Akt, p70S6K and p-p70S6K was determined by Western blotting. Then siRNA-Akt was used to determine that L-carnitine ameliorated cancer cachexia via the Akt/FOXO3/MaFbx. In vivo, the cancer cachexia model was established by subcutaneously transplanting CT26 cells into the left flanks of the BALB/c nude mice. After treated with L-carnitine, serum levels of IL-1, IL-6 and TNF-α, and the skeletal muscle content of MuRF1, MaFbx, FOXO3, p-FOXO3a, Akt, p-Akt, p70S6K and p-p70S6K were measured. Results L-carnitine increased the gastrocnemius muscle (GM) weight in the CT26-bearing cachexia mouse model and the cross-sectional fiber area of the GM and myotube diameters of C2C12 cells treated with TNF-α. Additionally, L-carnitine reduced the protein expression of MuRF1, MaFbx and FOXO3a, and increased the p-FOXO3a level in vivo and in vitro. Inhibition of Akt, upstream of FOXO3a, reversed the effects of L-carnitine on the FOXO3a/MaFbx pathway and myotube diameters, without affecting FOXO3a/MuRF-1. In addition to regulating the ubiquitination of muscle proteins, L-carnitine also increased the levels of p-p70S6K and p70S6K, which are involved in protein synthesis. Akt inhibition did not reverse the effects of L-carnitine on p70S6K and p-p70S6K. Hence, L-carnitine ameliorated cancer cachexia via the Akt/FOXO3/MaFbx and p70S6K pathways. Moreover, L-carnitine reduced the serum levels of IL-1 and IL-6, factors known to induce cancer cachexia. However, there were minimal effects on TNF-α, another inducer of cachexia, in the in vivo model. Conclusion These results revealed a novel mechanism by which L-carnitine protects muscle cells and reduces inflammation related to cancer cachexia.
format	article
author	Changpeng Wu Mingxing Zhu Zongliang Lu Yaowen Zhang Long Li Na Li Liangyu Yin He Wang Wei Song Hongxia Xu
author_facet	Changpeng Wu Mingxing Zhu Zongliang Lu Yaowen Zhang Long Li Na Li Liangyu Yin He Wang Wei Song Hongxia Xu
author_sort	Changpeng Wu
title	L-carnitine ameliorates the muscle wasting of cancer cachexia through the AKT/FOXO3a/MaFbx axis
title_short	L-carnitine ameliorates the muscle wasting of cancer cachexia through the AKT/FOXO3a/MaFbx axis
title_full	L-carnitine ameliorates the muscle wasting of cancer cachexia through the AKT/FOXO3a/MaFbx axis
title_fullStr	L-carnitine ameliorates the muscle wasting of cancer cachexia through the AKT/FOXO3a/MaFbx axis
title_full_unstemmed	L-carnitine ameliorates the muscle wasting of cancer cachexia through the AKT/FOXO3a/MaFbx axis
title_sort	l-carnitine ameliorates the muscle wasting of cancer cachexia through the akt/foxo3a/mafbx axis
publisher	BMC
publishDate	2021
url	https://doaj.org/article/2d96e81ea85d4a71b0776218586d425c
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L-carnitine ameliorates the muscle wasting of cancer cachexia through the AKT/FOXO3a/MaFbx axis

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