Loss of adult skeletal muscle stem cells drives age-related neuromuscular junction degeneration
Wenxuan Liu,
Alanna Klose,
Sophie Forman,
Nicole D Paris,
Lan Wei-LaPierre,
Mariela Cortés-Lopéz,
Aidi Tan,
Morgan Flaherty,
Pedro Miura,
Robert T Dirksen,
Joe V Chakkalakal
Affiliations
Wenxuan Liu
Department of Orthopaedics and Rehabilitation, Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, United States; Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, United States
Alanna Klose
Department of Orthopaedics and Rehabilitation, Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, United States
Sophie Forman
Department of Biology, University of Rochester, Rochester, United States
Department of Orthopaedics and Rehabilitation, Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, United States
Lan Wei-LaPierre
Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, United States
Mariela Cortés-Lopéz
Department of Biology, University of Nevada, Reno, United States
Aidi Tan
Bioinformatics Division and Center for Synthetic and Systems Biology, Tsinghua University, Beijing, China; TNLIST/Department of Automation, Tsinghua University, Beijing, China
Morgan Flaherty
Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, United States
Pedro Miura
Department of Biology, University of Nevada, Reno, United States
Robert T Dirksen
Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, United States
Department of Orthopaedics and Rehabilitation, Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, United States; Stem Cell and Regenerative Medicine Institute, University of Rochester Medical Center, Rochester, United States; The Rochester Aging Research Center, University of Rochester Medical Center, Rochester, United States
Neuromuscular junction degeneration is a prominent aspect of sarcopenia, the age-associated loss of skeletal muscle integrity. Previously, we showed that muscle stem cells activate and contribute to mouse neuromuscular junction regeneration in response to denervation (Liu et al., 2015). Here, we examined gene expression profiles and neuromuscular junction integrity in aged mouse muscles, and unexpectedly found limited denervation despite a high level of degenerated neuromuscular junctions. Instead, degenerated neuromuscular junctions were associated with reduced contribution from muscle stem cells. Indeed, muscle stem cell depletion was sufficient to induce neuromuscular junction degeneration at a younger age. Conversely, prevention of muscle stem cell and derived myonuclei loss was associated with attenuation of age-related neuromuscular junction degeneration, muscle atrophy, and the promotion of aged muscle force generation. Our observations demonstrate that deficiencies in muscle stem cell fate and post-synaptic myogenesis provide a cellular basis for age-related neuromuscular junction degeneration and associated skeletal muscle decline.
