Lack of Tgfbr1 and Acvr1b synergistically stimulates myofibre hypertrophy and accelerates muscle regeneration

Michele M. G. Hillege, Andi Shi, Ricardo A. Galli, Gang Wu, Philippe Bertolino, Willem M. H. Hoogaars, Richard T. Jaspers*, Christopher L-H Huang

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

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    Abstract

    In skeletal muscle, transforming growth factor-beta (TGF-beta) family growth factors, TGF-beta 1 and myostatin, are involved in atrophy and muscle wasting disorders. Simultaneous interference with their signalling pathways may improve muscle function; however, little is known about their individual and combined receptor signalling. Here, we show that inhibition of TGF-beta signalling by simultaneous muscle-specific knockout of TGF-beta type I receptors Tgfbr1 and Acvr1b in mice, induces substantial hypertrophy, while such effect does not occur by single receptor knockout. Hypertrophy is induced by increased phosphorylation of Akt and p70S6K and reduced E3 ligases expression, while myonuclear number remains unaltered. Combined knockout of both TGF-beta type I receptors increases the number of satellite cells, macrophages and improves regeneration post cardiotoxin-induced injury by stimulating myogenic differentiation. Extra cellular matrix gene expression is exclusively elevated in muscle with combined receptor knockout. Tgfbr1 and Acvr1b are synergistically involved in regulation of myofibre size, regeneration, and collagen deposition.

    Original languageEnglish
    Article number77610
    Number of pages32
    JournaleLife
    Volume11
    DOIs
    Publication statusPublished - 24-Mar-2022

    Keywords

    • TGF-beta
    • myostatin
    • type I receptor
    • hypertrophy
    • injury
    • skeletal muscle
    • Mouse
    • TRANSFORMING-GROWTH-FACTOR
    • SATELLITE CELL-PROLIFERATION
    • INHIBITS MYOBLAST DIFFERENTIATION
    • CONNECTIVE-TISSUE FIBROBLASTS
    • SKELETAL-MUSCLE
    • FACTOR-BETA
    • FIBER SIZE
    • FACTOR-I
    • MYOSTATIN
    • EXPRESSION

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