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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Larouche, JA; Mohiuddin, M; Choi, JJ; Ulintz, PJ; Fraczek, P; Sabin, K; Pitchiaya, S; Kurpiers, SJ; Castor-Macias, J; Liu, W; Hastings, RL; Brown, LA; Markworth, JF; De Silva, K; Levi, B; Merajver, SD; Valdez, G; Chakkalakal, JV; Jang, YC; Brooks, SV; Aguilar, CA

Published Date

  • July 29, 2021

Published In

Volume / Issue

  • 10 /

PubMed ID

  • 34323217

Pubmed Central ID

  • PMC8360658

Electronic International Standard Serial Number (EISSN)

  • 2050-084X

Digital Object Identifier (DOI)

  • 10.7554/eLife.66749

Language

  • eng

Conference Location

  • England