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

ABSTRACT Transforming growth factor-β (TGF-β) signaling is associated with progressive skeletal muscle wasting and fibrosis, while double knockout of TGF-β type I receptors Acvr1b and Tgfbr1 results in hypertrophy. Gaining insights in how myofibre-specific knockout of these receptors affects muscle transcriptome, strength and mitochondrial activity could aid in the development of therapeutic interventions to improve muscle function. Here, we show that 3 months of myofibre-specific knockout of both receptors (dKO) in mice induced a 1.6-fold increase in gastrocnemius medialis mass and a 1.3-fold increase in maximal force. Soleus muscle mass and maximal force both increased 1.2-fold in dKO mice. Muscle hypertrophy in dKO mice was accompanied by a proportional increase in succinate dehydrogenase enzyme activity. Single receptor knockout caused minor phenotypical alterations. Transcriptome analyses revealed that gastrocnemius medialis had 1811 and soleus had 295 differentially expressed genes, mainly related to muscle contraction, hypertrophy, filament organization and oxidative metabolism. Hgf and Sln genes were strongly upregulated in both muscles of dKO mice, while Sntb1 was downregulated. This in combination of transcriptional changes are associated with muscle hypertrophy and increased mitochondrial biosynthesis. Our study highlights that myofibre-specific interference with both TGF-β type I receptors concurrently stimulates myofibre hypertrophy and mitochondrial activity.