Lack ofTgfbr1andAcvr1bsynergistically stimulates myofibre hypertrophy and accelerates muscle regeneration

Abstract

TGF-β, myostatin and activin A are involved in regulation of muscle mass and contribute to the progressive pathology of muscle wasting disorders by regulating muscle fibrosis and inhibiting satellite cell proliferation and differentiation. Inhibition of TGF-β signalling through knockout of TGF-β type I receptors Tgfbr1 and Acvr1b may be a promising therapeutic approach. Here we show how muscle morphology and early muscle regeneration are altered in a myofibre specific knockout of Tgfbr1 and/or Acvr1b. Simultaneous receptor knockout caused nearly doubling of tibialis anterior muscle size via a reduction in protein degradation via E3 ligases and increased phosphorylation of Akt and p70S6K, while the number of myonuclei remained unaltered. Four days post injury, CSA of regenerating myofibres lacking both receptors was substantially increased compared to that of fibres lacking either Tgfbr1 or Acvr1b. This was accompanied by an increased number of satellite cells at day 0 and increased myogenic gene expression. ECM gene expression was exclusively elevated in muscle with combined receptor knockout. These findings indicate simultaneous Tgfbr1 and Acvr1b knockout results in sizable muscle hypertrophy and accelerates early muscle regeneration.

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 52 . Here, three months after inducible knockout of both type I receptors, FCSA was increased in both fast-and slow-type muscles.…”