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

Abstract

In skeletal muscle, transforming growth factor-β (TGF-β) family growth factors, TGF-β1 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-β signalling by simultaneous muscle-specific knockout of TGF-β 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-β 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.

Myofibre-specific knockout of TGF-β type I receptors triggers muscle hypertrophy and promotes contraction and oxidative metabolism

“…In addition to the largest number of DEGs, double knockout of TGF-β type I receptors induced the largest hypertrophy in fast-type muscle. Previously we have shown that 5 weeks after tamoxifen-induced knockout of both TGF-β type I receptors in skeletal muscle, type IIB myofibre CSA of tibialis anterior muscle was increased by twofold, while type I myofibre CSA was not changed 53 . Here, three months after inducible knockout of both type I receptors, FCSA was increased in both fast-and slow-type muscles.…”

SETDB1 modulates the TGFβ response in Duchenne muscular dystrophy myotubes

“…Although FAPs and macrophages have been described as major TGFβ sources, and as fibrosis and inflammation effectors, myofibers are also responsive to TGFβ1 and have been shown to participate in TGFβ/SMAD response during muscle regeneration in vivo ( 28 , 29 ). TGFβ–induced fibrosis is a key pathological feature in muscle diseases, such as DMD, and TGFβ overactivation worsens muscle degeneration by preventing proper repair.…”

SETDB1 modulates the TGFβ response in Duchenne muscular dystrophy myotubes

“…Although FAPs and macrophages have been described as major TGFβ sources, and as fibrosis and inflammation effectors, myofibers are also responsive to TFGβ1 and have been shown to participate in TGFβ/SMAD response during muscle regeneration in vivo ( 28, 29 ). TGFβ-induced fibrosis is a key pathological feature in muscle disease, such as DMD, and TGFβ overactivation worsens muscle degeneration by preventing proper repair.…”