Metavinculin mediates differentiation cues into myogenic gene expression.

Isoform switching in deciphering differentiation signals into myogenic transcriptional output remains unexplored. Here, we report a distinct function of muscle-specific metavinculin isoform in switching canonical to non-canonical Wnt-pathways to establish skeletal muscle differentiation. Metavinculin expression is specifically associated with muscle differentiation, regeneration and absent in proliferating myoblasts. During differentiation, metavinculin-specific exon retention is facilitated by the direct binding of Rbfox1 to its downstream intron. Depletion of metavinculin impairs skeletal muscle differentiation, while its ectopic expression induces genes associated with differentiation even in proliferating myoblasts. Subsequent results revealed that pharmacological activation of canonical Wnt impedes muscle differentiation, whereas its inhibition stimulates differentiation. Canonical Wnt inhibition or ectopic non-canonical Wnt7b expression restores muscle differentiation programs in metavinculin-depleted cells. These results indicates a dynamic interplay between Rbfox1-generated metavinculin and Wnt-signaling pathways. This advancement sheds light on the intricate molecular mechanisms underlying skeletal muscle differentiation and suggests potential therapeutic targets for muscle-related disorders.