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

Flavia A. Graca, Mamta Rai, Liam C. Hunt, Anna Stephan, Yong-Dong Wang, Brittney Gordon, Ruishan Wang, Giovanni Quarato, Beisi Xu, Yiping Fan, Myriam Labelle and Fabio Demontis ()
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Flavia A. Graca: St. Jude Children’s Research Hospital
Mamta Rai: St. Jude Children’s Research Hospital
Liam C. Hunt: St. Jude Children’s Research Hospital
Anna Stephan: St. Jude Children’s Research Hospital
Yong-Dong Wang: St. Jude Children’s Research Hospital
Brittney Gordon: St. Jude Children’s Research Hospital
Ruishan Wang: St. Jude Children’s Research Hospital
Giovanni Quarato: St. Jude Children’s Research Hospital
Beisi Xu: St. Jude Children’s Research Hospital
Yiping Fan: St. Jude Children’s Research Hospital
Myriam Labelle: St. Jude Children’s Research Hospital
Fabio Demontis: St. Jude Children’s Research Hospital

Nature Communications, 2022, vol. 13, issue 1, 1-22

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30120-1

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