Murine muscle stem cell response to perturbations of the neuromuscular junction are attenuated with aging

eLife

Jesus Castor-Macias¹  Kaitlyn Sabin¹  Sarah J Kurpiers¹  Jacqueline A Larouche¹  Kanishka De Silva¹  Paula Fraczek¹  Carlos A Aguilar²  Peter J Ulintz³  Susan V Brooks⁴  Sofia D Merajver⁵  Lemuel A Brown⁶  James F Markworth⁶  Wenxuan Liu⁷  Joe V Chakkalakal⁷  Benjamin Levi⁸  Gregorio Valdez⁹  Robert Louis Hastings⁹  Sethuramasundaram Pitchiaya^1,10  Mahir Mohiuddin^1,11  Young C Jang^1,11  Jeongmoon J Choi^1,11 

[1] Department of Biomedical Engineering, University of Michigan, Ann Arbor, United States;Biointerfaces Institute, University of Michigan, Ann Arbor, United States;Department of Biomedical Engineering, University of Michigan, Ann Arbor, United States;Biointerfaces Institute, University of Michigan, Ann Arbor, United States;Childrens Research Institute and Center for Mineral Metabolism, Dallas, United States;Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, United States;Department of Biomedical Engineering, University of Michigan, Ann Arbor, United States;Biointerfaces Institute, University of Michigan, Ann Arbor, United States;Internal Medicine-Hematology/Oncology, University of Michigan, Ann Arbor, United States;Department of Biomedical Engineering, University of Michigan, Ann Arbor, United States;Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, United States;Department of Biomedical Engineering, University of Michigan, Ann Arbor, United States;Internal Medicine-Hematology/Oncology, University of Michigan, Ann Arbor, United States;Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, United States;Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, United States;Department of Biomedical Engineering, University of Rochester Medical Center, Rochester, United States;Wilmot Cancer Institute, Stem Cell and Regenerative Medicine Institute, and The Rochester Aging Research Center, University of Rochester Medical Center, Rochester, United States;Department of Surgery, University of Texas Southwestern, Dallas, United States;Childrens Research Institute and Center for Mineral Metabolism, Dallas, United States;Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, United States;Departmentof Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, United States;Center for Translational Neuroscience, Robert J. and Nancy D. Carney Institute for Brain Science and Brown Institute for Translational Science, Brown University, Providence, United States;Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, United States;Parker H. Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, United States;School of Biological Sciences, Georgia Institute of Technology, Atlanta, United States;Wallace Coulter Departmentof Biomedical Engineering, Georgia Institute of Technology, Atlanta, United States;

关键词: single cell RNA-seq;    aging;    neuromuscular junction;    synapse;    Mouse;   

DOI  :  10.7554/eLife.66749

来源: eLife Sciences Publications, Ltd

【 摘 要 】

During aging and neuromuscular diseases, there is a progressive loss of skeletal muscle volume and function impacting mobility and quality of life. Muscle loss is often associated with denervation and a loss of resident muscle stem cells (satellite cells or MuSCs); however, the relationship between MuSCs and innervation has not been established. Herein, we administered severe neuromuscular trauma to a transgenic murine model that permits MuSC lineage tracing. We show that a subset of MuSCs specifically engraft in a position proximal to the neuromuscular junction (NMJ), the synapse between myofibers and motor neurons, in healthy young adult muscles. In aging and in a mouse model of neuromuscular degeneration (Cu/Zn superoxide dismutase knockout – Sod1-/-), this localized engraftment behavior was reduced. Genetic rescue of motor neurons in Sod1-/- mice reestablished integrity of the NMJ in a manner akin to young muscle and partially restored MuSC ability to engraft into positions proximal to the NMJ. Using single cell RNA-sequencing of MuSCs isolated from aged muscle, we demonstrate that a subset of MuSCs are molecularly distinguishable from MuSCs responding to myofiber injury and share similarity to synaptic myonuclei. Collectively, these data reveal unique features of MuSCs that respond to synaptic perturbations caused by aging and other stressors.

【 授权许可】

CC BY