A novel CARM1–HuR axis involved in muscle differentiation and plasticity misregulated in spinal muscular atrophy

Abstract

Spinal muscular atrophy (SMA) is characterized by the loss of alpha motor neurons in the spinal cord and a progressive muscle weakness and atrophy. SMA is caused by loss-of-function mutations and/or deletions in the survival of motor neuron (SMN) gene. The role of SMN in motor neurons has been extensively studied, but its function and the consequences of its loss in muscle has also emerged as a key aspect of SMA pathology. In this study, we explore the molecular mechanisms involved in muscle defects in SMA. First, we show in C2C12 myoblasts, that arginine methylation by CARM1 controls myogenic differentiation. More specifically, the methylation of HuR on K217 regulates HuR levels and subcellular localization during myogenic differentiation, and the formation of myotubes. Furthermore, we demonstrate that SMN and HuR interact in C2C12 myoblasts. Interestingly, the SMA-causing E134K point mutation within the SMN Tudor domain, and CARM1 depletion, modulate the SMN-HuR interaction. In addition, using the Smn2B/− mouse model, we report that CARM1 levels are markedly increased in SMA muscles and that HuR fails to properly respond to muscle denervation, thereby affecting the regulation of its mRNA targets. Altogether, our results show a novel CARM1-HuR axis in the regulation of muscle differentiation and plasticity as well as in the aberrant regulation of this axis caused by the absence of SMN in SMA muscle. With the recent developments of therapeutics targeting motor neurons, this study further indicates the need for more global therapeutic approaches for SMA.

Sex-Specific Impact of CARM1 in Skeletal Muscle Adaptations to Exercise

“…Overall, this study demonstrates that CARM1 mKO has minimal effects on skeletal muscle adaptations to VWR, despite the significant effect of the enzyme on sex-specific running volume and mitochondrial plasticity. Given the broad importance of PRMT (5,64), and CARM1 specifically (7,14,65–69), in determining, maintaining, and remodeling skeletal muscle biology, the similar adaptations to exercise observed between WT and mKO animals in this study may be explained by substrate scavenging by other PRMT; however, this hypothesis will require dedicated testing in future experiments. Further investigation of sex-specific changes to CARM1 expression and activity during conditions that induce skeletal muscle plasticity would aid in increasing our understanding of the role this enzyme plays in muscle biology.…”