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The myokine Fibcd1 is an endogenous determinant of myofiber size and mitigates cancer-induced myofiber atrophy.

ABSTRACT: Decline in skeletal muscle cell size (myofiber atrophy) is a key feature of cancer-induced wasting (cachexia). In particular, atrophy of the diaphragm, the major muscle responsible for breathing, is an important determinant of cancer-associated mortality. However, therapeutic options are limited. Here, we have used Drosophila transgenic screening to identify muscle-secreted factors (myokines) that act as paracrine regulators of myofiber growth. Subsequent testing in mouse myotubes revealed that mouse Fibcd1 is an evolutionary-conserved myokine that preserves myofiber size via ERK signaling. Local administration of recombinant Fibcd1 (rFibcd1) ameliorates cachexia-induced myofiber atrophy in the diaphragm of mice bearing patient-derived melanoma xenografts and LLC carcinomas. Moreover, rFibcd1 impedes cachexia-associated transcriptional changes in the diaphragm. Fibcd1-induced signaling appears to be muscle selective because rFibcd1 increases ERK activity in myotubes but not in several cancer cell lines tested. We propose that rFibcd1 may help reinstate myofiber size in the diaphragm of patients with cancer cachexia.

SUBMITTER: Graca FA

PROVIDER: S-EPMC9061726 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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The myokine Fibcd1 is an endogenous determinant of myofiber size and mitigates cancer-induced myofiber atrophy.

Graca Flavia A FA Rai Mamta M Hunt Liam C LC Stephan Anna A Wang Yong-Dong YD Gordon Brittney B Wang Ruishan R Quarato Giovanni G Xu Beisi B Fan Yiping Y Labelle Myriam M Demontis Fabio F

Nature communications 20220502 1

Decline in skeletal muscle cell size (myofiber atrophy) is a key feature of cancer-induced wasting (cachexia). In particular, atrophy of the diaphragm, the major muscle responsible for breathing, is an important determinant of cancer-associated mortality. However, therapeutic options are limited. Here, we have used Drosophila transgenic screening to identify muscle-secreted factors (myokines) that act as paracrine regulators of myofiber growth. Subsequent testing in mouse myotubes revealed that ...[more]

PMID: 35501350

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Project description:BackgroundSodium-glucose cotransporter 2 inhibitors (SGLT2i) are commonly used in the management of type 2 diabetes mellitus (T2DM) and have been found to worsen the reduction of skeletal muscle mass in individuals with T2DM. This study aims to examine the potential of exercise in mitigating the skeletal muscle atrophy induced by SGLT2i treatment.MethodsA rat model of T2DM (40 male Sprague-Dawley rats; T2DM induced by a combination of high-fat diet and streptozotocin) was used to examine the effects of six-week treatment with Dapagliflozin (DAPA, SGLT2i) in combination with either aerobic exercise (AE) or resistance training (RT) on skeletal muscle. T2DM-eligible rats were randomized into the T2DM control group (CON, n = 6), DAPA treatment group (DAPA, n = 6), DAPA combined with aerobic exercise intervention group (DAPA + AE, n = 6), and DAPA combined with resistance training intervention group (DAPA + RT, n = 6). To assess the morphological changes in skeletal muscle, myosin ATPase and HE staining were performed. mRNA expression levels of Atrogin-1, MuRF1, and Myostatin were determined using quantitative PCR. Furthermore, protein expression levels of AKT, p70S6K, mTOR, FoXO1/3A, NF-κB, and MuRF1 were examined through western blotting.ResultsBoth the administration of DAPA alone and the combined exercise intervention with DAPA resulted in significant reductions in blood glucose levels and body weight in rats. However, DAPA alone administration led to a decrease in skeletal muscle mass, whereas RT significantly increased skeletal muscle mass and muscle fiber cross-sectional area. The DAPA + RT group exhibited notable increases in both total protein levels and phosphorylation levels of AKT and p70S6K in skeletal muscle. Moreover, the DAPA, DAPA + AE, and DAPA + RT groups demonstrated downregulation of protein expression (FoXO1/3A) and mRNA levels (Atrogin-1, MuRF1, and Myostatin) associated with muscle atrophy.ConclusionsOur findings provide support for the notion that dapagliflozin may induce skeletal muscle atrophy through mechanisms unrelated to protein metabolism impairment in skeletal muscle, as it does not hinder protein metabolic pathways while reduces muscle atrophy-related genes. Additionally, our observations reveal that RT proves more effective than AE in enhancing skeletal muscle mass and muscle fiber cross-sectional area in rats with T2DM by stimulating protein anabolism within the skeletal muscle.

Dataset Information

The myokine Fibcd1 is an endogenous determinant of myofiber size and mitigates cancer-induced myofiber atrophy.

Publications

The myokine Fibcd1 is an endogenous determinant of myofiber size and mitigates cancer-induced myofiber atrophy.

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