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

Jacqueline A. Larouche, Mahir Mohiuddin, Jeongmoon J. Choi, Peter J. Ulintz, Paula Fraczek, Kaitlyn Sabin, Sethuramasundaram Pitchiaya, Sarah J. Kurpiers, Jesus Castor-Macias, Wenxuan Liu, Robert Louis Hastings, Lemuel A. Brown, James F. Markworth, Kanishka de Silva, Benjamin D. Levi, Sofia D. Merajver, Gregorio Valdez, Joe V. Chakkalakal, Young C. Jang, Susan V. BrooksCarlos A. Aguilar

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere66749
JournaleLife
Volume10
DOIs
StatePublished - Jul 2021

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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