miR-206 enforces a slow muscle phenotype

Striated muscle is a highly specialized collection of tissues that have different contractile properties depending on their functional roles. These properties derive from differential gene expression, including sarcomeric genes such as myosin heavy chains (MyHCs) and metabolic genes that coordinate energy demands with the contractile machinery. Although muscle fiber types are established shortly after birth, there is lifelong plasticity that facilitates adaptation to both physiologic and pathologic stimuli. Functional adaptation requires molecular adaptation, and this is partially provided by miRNA-mediated post-transcriptional regulation. Several miRNAs are specific to muscle, including miR-206, which is particularly associated with slow oxidative muscles and is up-regulated in conditions that shift fast muscles towards a slower phenotype. We sought to determine whether miR-206 is a driver of the slow muscle phenotype or merely a terminal outcome. We found that miR-206 expression increases in both physiologic (female sex and endurance exercise) and pathologic conditions (muscular dystrophy and response to acute injury) that promote the slow phenotype. We also found that the predominantly slow soleus displays a faster phenotype in miR-206 knockout mice. Left ventricles of these animals also have a faster MyHC profile that is accompanied by dilation and systolic dysfunction. Interestingly, these phenotypes were male-specific. Our data indicate that miR-206 is necessary to enforce the slow straited muscle phenotype and that miR-206 plays a key role in sexual dimorphisms in cardiac and skeletal muscle.