Inducible depletion of adult skeletal muscle stem cells impairs the regeneration of neuromuscular junctions
Wenxuan Liu,
Lan Wei-LaPierre,
Alanna Klose,
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, Genetics, Genomics and Development Graduate Program, University of Rochester Medical Center, Rochester, United States
Lan Wei-LaPierre
Department of Pharmacology and Physiology, 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
Robert T Dirksen
Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, United States
Joe V Chakkalakal
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
Skeletal muscle maintenance depends on motor innervation at neuromuscular junctions (NMJs). Multiple mechanisms contribute to NMJ repair and maintenance; however muscle stem cells (satellite cells, SCs), are deemed to have little impact on these processes. Therefore, the applicability of SC studies to attenuate muscle loss due to NMJ deterioration as observed in neuromuscular diseases and aging is ambiguous. We employed mice with an inducible Cre, and conditionally expressed DTA to deplete or GFP to track SCs. We found SC depletion exacerbated muscle atrophy and type transitions connected to neuromuscular disruption. Also, elevated fibrosis and further declines in force generation were specific to SC depletion and neuromuscular disruption. Fate analysis revealed SC activity near regenerating NMJs. Moreover, SC depletion aggravated deficits in reinnervation and post-synaptic morphology at regenerating NMJs. Therefore, our results propose a mechanism whereby further NMJ and skeletal muscle decline ensues upon SC depletion and neuromuscular disruption.
