Muscle fibro/adipogenic progenitor (FAP) mitochondria transfer in neuromuscular degeneration in ALS in a pilot mouse study


Translational Research

Poster Number: 331


Austin Lee, BS, University of California, San Francisxo, Isha Pema, University of California, Berkeley, Brian Feeley, MD, University of California, San Francisco, Xuhui Liu, MD, University of California, San Francisco

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neurons (MNs) degeneration and severe muscle atrophy. Recent studies suggest that skeletal muscle, especially the neuromuscular junction (NMJ), plays an important role in the pathogenesis of ALS. Fibro/adipogenic progenitor (FAP) cells are a population of mesenchymal progenitor cells that play a crucial role in muscle homeostasis and NMJ stabilization. Our recent study found that FAPs store large numbers of mitochondria that can be transferred to nearby myocytes to facilitate muscle regeneration. However, intercellular mitochondrial transfer has not been reported in neuromuscular degeneration in ALS. In this study, we generated two novel transgenic mouse strains to study the role of FAPs in ALS. FAP reporter ALS mice were generated by crossing PDGFRa-eGFP reporter mice with SOD1G93A ALS mice. Inducible FAP mitochondria reporter ALS mice were generated by crossing PDGFRa-CreERT and MitoTag (Rosa26-CAG-LSL-GFP-OMM) mice with PDGFRa-reporter/SOD1G93A ALS mice. Both PDGFRa-reporter/SOD1G93A and PDGFRa-CreERT/Mito-tag/PDGFRa-reporter/SOD1G93A mice showed similar neuromuscular degenerative phenotype as SOD1G93A mice and developed hindlimb paralysis at the age about 4-5 months. Both FAP-reporter and FAP-mitotag ALS mice and their littermate wildtype controls (n=3-4 for each strain) were sacrificed at 4.5 months of age and Tibialis Anterior (TA) muscles were harvested for histological analysis, which showed an increased number of FAPs in TA muscles in ALS mice compared to wildtype control. Confocal microscopy showed an abundance of FAP-derived mitochondrial transfer to myotubes and NMJs in ALS mice. Our results show that FAPs proliferate in amyotrophic muscle and donate mitochondria to surrounding amyotrophic myofibers and degenerative NMJs. Targeting FAPs and their mitochondrial transfer may inform new therapeutic approaches to reduce muscular degeneration and improve the quality of life in ALS patients.