Talk abstracts
Talk on Tuesday 03:15-03:30pm submitted by J. Spencer Hauck
Mineralocorticoid receptor myofiber knockout and antagonists lead to complementary beneficial effects on muscular dystrophy membrane integrity, strength, and fibrosis
J. Spencer Hauck (Molecular, Cellular, and Developmental Biology), Jeovanna Lowe, Neha Rastogi, Kevin E. McElhanon, Jennifer M. Petrosino, Kyra K. Peczkowski, Sarah A. Swager, Ashlee, N. Chadwick, Jonathan G. Zins, Sarah Sawger, Federica Accornero, Paul M. L. Janssen, Noah L. Weisleder, Jill A. Rafael-Fortney (Physiology and Cell Biology Department, The Ohio State University)
Abstract:
Mineralocorticoid receptor (MR) antagonists have been used clinically for decades to treat cardiovascular diseases. MR antagonists have been recently found to be cardioprotective for Duchenne muscular dystrophy (DMD) patients. MR antagonists show preclinical efficacy not only for heart in DMD mouse models, but also improve skeletal muscle force, muscle membrane integrity, and decrease myofiber degeneration. Since MR are present in many cell types in the muscle microenvironment including immune cells, endothelial cells, fibroblasts, and myofibers, it is important to define cell-intrinsic functions in each cell type to ultimately optimize antagonist efficacy. We generated a conditional knockout of MR in myofibers and quantified cell-intrinsic mechanistic effects on functional and histological parameters in a DMD mouse model. In contrast to in vivo MR antagonist treatment, muscle membrane integrity was not improved in myofiber MR conditional knockout mice. Surprisingly, acute ex vivo application of MR antagonist in a laser injury assay led to improvement in muscle membrane integrity independent of myofiber MR. Skeletal muscle MR deficiency led to improved respiratory muscle force generation and fatigue at 12 weeks-of-age and reduced diaphragm fibrosis at 1 year-of-age. These data demonstrate that MR antagonists are efficacious to dystrophic skeletal muscles through both myofiber MR intrinsic and extrinsic functions. The interplay of immune cell infiltration, fibrosis, and myofiber regeneration in acute muscle injury in myofiber MR conditional knockout and MR antagonist treated mice will be independently investigated. The comparison between acute and chronic muscle injuries will allow dissection of myofiber MR and MR antagonism functions on muscle microenvironment regulation. These data support that MR antagonists may be applicable for treating more general muscle weakness and possibly other conditions that result from cellular injury.
References:
This work was supported by National Institutes of Health R01 NS082868, T32 NS077984-05, and R01 HL116533.
Keywords: Mineralocorticiod Receptor, Myofiber, Muscular Dystrophy