Muscle development and regeneration controlled by AUF1-mediated stage-specific degradation of fate-determining checkpoint mRNAs

Significance

Muscle-wasting diseases are due in part to improper regulation of mRNA stability. Mutations in the mRNA decay protein AUF1 are linked to a specific form of muscle-wasting disease known as limb girdle muscular dystrophy that affects the muscles of the limbs and torso. How AUF1 is involved in regulating or promoting muscle regeneration is largely unknown. Here, we demonstrate that AUF1 controls all of the major stages of muscle development and regeneration, from control of the muscle stem (satellite) cell differentiation program through the development of mature muscle fibers, by selectively targeting for rapid degradation the major differentiation checkpoint mRNAs that block entry into each next phase of muscle development, thereby promoting each stage of muscle development.

Abstract

AUF1 promotes rapid decay of mRNAs containing 3′ untranslated region (3′UTR) AU-rich elements (AREs). AUF1 depletion in mice accelerates muscle loss and causes limb girdle muscular dystrophy. Here, we demonstrate that the selective, targeted degradation by AUF1 of key muscle stem cell fate-determining checkpoint mRNAs regulates each stage of muscle development and regeneration by reprogramming each myogenic stage. Skeletal muscle stem (satellite) cell explants show that Auf1 transcription is activated with satellite cell activation by stem cell regulatory factor CTCF. AUF1 then targets checkpoint ARE-mRNAs for degradation, progressively reprogramming the transcriptome through each stage of myogenesis. Transition steps in myogenesis, from stem cell proliferation to differentiation to muscle fiber development, are each controlled by fate-determining checkpoint mRNAs, which, surprisingly, were found to be controlled in their expression by AUF1-targeted mRNA decay. Checkpoint mRNAs targeted by AUF1 include Twist1, decay of which promotes myoblast development; CyclinD1, decay of which blocks myoblast proliferation and initiates differentiation; and RGS5, decay of which activates Sonic Hedgehog (SHH) pathway-mediated differentiation of mature myotubes. AUF1 therefore orchestrates muscle stem cell proliferation, self-renewal, myoblast differentiation, and ultimately formation of muscle fibers through targeted, staged mRNA decay.