Skeletal Muscle Phenotype-Specific Effects of ACVR1B and TGFBR1 Receptor Signalling on Muscle Transcriptome, Force generation and Metabolism

ABSTRACT Transforming growth factor-β (TGF-β) signalling is associated with progressive muscle wasting. Targeting TGF-β type I receptors Acvr1b and Tgfbr1 in skeletal muscle results in excessive muscle hypertrophy. However, how myofibre-specific knockout of these receptors affects muscle transcriptome, strength and oxidative metabolisms is unknown. Here, we show that 3 months of myofibre-specific knockout of both receptors (dKO) in fast, low oxidative gastrocnemius medialis muscles induced a 1.6-fold increase in muscle mass while maximal force was increased disproportionally (i.e. specific force was reduced by 23%). In contrast, slow, high oxidative soleus muscle in dKO mice showed only a 1.2-fold increase in muscle mass and maximal force was increased proportionally. Single receptor knockout caused minor phenotypical alterations. Transcriptome analyses showed that gastrocnemius medialis muscles had 1811 and soleus muscles had 295 differentially expressed genes which were mainly related to muscle contraction, hypertrophy, filament organization and oxidative metabolism. Myofibre hypertrophy in both dKO muscles was, strikingly, accompanied by a proportional increase in succinate dehydrogenase enzyme activity. Our results show that myofibre-specific interference with both TGF-β type I receptors concurrently stimulates myofibre hypertrophy and oxidative metabolic capacity.