ABSTRACT: Key components of skeletal muscle that regulate excitability and excitation-contraction coupling (ECC) undergo major shifts of isoform expression during development. This process of perinatal ECC remodeling is highly conserved throughout vertebrate evolution and results mainly from post-transcriptional mechanisms in which alternative splicing of specific exons for ClC-1, CaV1.1, RyR1 and SERCA1 occurs. In myotonic dystrophy (DM), these splicing switches revert to their fetal set points due to sequestration of MBNL splicing factors in nuclear RNA foci. We used gene editing to recreate individual DM splicing defects in mice and systematically analyzed mice for effects in isolation and in combination through breeding. Our preliminary studies indicate that loss of ClC-1 function combined with CaV1.1 exon 29 exclusion (Cav1.1∆e29), comparable to that observed in DM patients, results in severe muscle weakness and respiratory deficits and is lethal in mice by age ~9 wks. This effect is rescued by long-term treatment by oral feeding with a Food & Drug Administration (FDA) approved calcium channel blocker. Here we propose studies to define mechanisms and explore the possibility that drug treatments that target myotonia and Cav1.1 channels can mitigate muscle weakness in DM. In Aim 1 we will investigate the mechanism for the early demise of myotonic Cav1.1∆e29 mice, including the study of how Cav1.1∆e29 channels impact membrane excitability and Ca2+ homeostasis, and downstream effectors that include calpain, transcription and mitochondrial health. Further, we will determine if myotonic Cav1.1∆e29 mice exhibit skeletal muscle weakness and altered respiratory function. In Aim 2 we will treat myotonic Cav1.1∆e29 mice by oral feeding of FDA approved drugs that target the calcium channel or myotonia by factorial design (one, the other, both or neither) to see which treatment is most effective at extending life and improving muscle and respiratory function. In Aim 3 we will move the treatment into a CUG repeat expansion DM1 mouse model that exhibits severe muscle weakness, myopathic features and shortened lifespan. We will use a series of non- invasive techniques to measure muscle and respiratory function to determine treatment benefit in longitudinal studies. The ultimate goal of this proposal is to identify DM1 therapeutic interventions that can be rapidly transitioned to the clinic.