Inhibition of inflammatory CCR2 signaling promotes aged muscle regeneration and strength recovery after injury

Abstract

Muscle regeneration depends on a robust albeit transient inflammatory response. Persistent inflammation is a feature of age-related regenerative deficits, yet the underlying mechanisms are poorly understood. Here, we find inflammatory-related CC-chemokine-receptor 2 (Ccr2) expression in non-hematopoietic myogenic progenitors (MPs) during regeneration. After injury, the expression of Ccr2 in MPs corresponds to the levels of its ligands, the chemokines Ccl2, 7, and 8. We find stimulation of Ccr2-activity inhibits MP fusion and contribution to myofibers. This occurs in association with increases in MAPKp38δ/γ signaling, MyoD phosphorylation, and repression of the terminal myogenic commitment factor Myogenin. High levels of Ccr2-chemokines are a feature of regenerating aged muscle. Correspondingly, deletion of Ccr2 in MPs is necessary for proper fusion into regenerating aged muscle. Finally, opportune Ccr2 inhibition after injury enhances aged regeneration and functional recovery. These results demonstrate that inflammatory-induced activation of Ccr2 signaling in myogenic cells contributes to aged muscle regenerative decline.

Transcriptomic meta‐analysis of disuse muscle atrophy vs. resistance exercise‐induced hypertrophy in young and older humans

“…Caspases stimulate essential proteolysis, removing non‐functional myofibrillar proteins to facilitate deposition of new proteins for hypertrophic adaptation, 101 such that impaired caspase transcript activation in ageing could hinder effective sarcomere remodelling during RET. Moreover, two of the top up‐regulated genes in young RET muscle were inflammatory chemokine transcripts CCL8 and CXCL10 , the abnormal regulation of which associates with ageing muscle regenerative decline ( CCL8 102 ) and impaired macrophage > satellite‐cell‐mediated myogenesis ( CXCL10 103 ). Overall, a consistent pattern emerges where failure to mount proper RET‐induced inflammatory responses could hinder ageing muscle regenerative capacity and growth responses 104 …”

Chemoradiation impairs myofiber hypertrophic growth in a pediatric tumor model

“…Surprisingly, a single injection of vincristine at 4-5 weeks of age induced loss of myonuclei in SOL as opposed to EDL muscles; however, this was not accompanied by a loss of SCs. Thus, the loss of myonuclei in SOL myofibers after prepubertal vincristine treatment likely involves mechanisms that regulate active SC function and/or myogenic progenitor differentiation 45,61,62 . Vincristine has also previously been shown to impair physiological skeletal muscle function in rats in a dose dependent manner, and its known toxicity profile manifests as neuropathy and muscle atrophy in humans 20,63,64 .…”

“…Skeletal muscle is endowed with a population of Pax7-expressing resident stem cells called satellite cells (SCs), which are a principal source of myonuclei that contribute to embryonic and early postnatal growth as well as muscle regeneration 30,[45][46][47][48] . Since we observed a loss of myonuclei, particularly after prepubertal radiation, EDL and SOL muscles were processed for Pax7 immunostaining to assess SC content at 3 weeks post-treatment.…”

Strength in numbers: Large-scale integration of single-cell transcriptomic data reveals rare, transient muscle progenitor cell states in muscle regeneration

“…We provide a scalable pipeline of alignment, quality control, processing, and integration to unify sc/snRNAseq data from diverse experimental settings and techniques for common analysis. We annotated cell subtypes using a curated panel of 115 marker genes from the literature 11,15,16,28,36,[45][46][47][48][49][50][51][52][53][54][55] . This approach provides a consensus resource of cell-type annotations for the skeletal muscle field, which may enable more consistent analyses across studies and allow for more clear identification of cell subpopulations.…”