Activation of skeletal muscle–resident glial cells upon nerve injury

Abstract

Here, we report on the identification of Itga7-expressing muscle resident glial cells activated by loss of NMJ integrity. Gene expression analysis at bulk and single cell level revealed that these cells are distinct from Itga7-expressing muscle satellite cells. We show that a selective activation and expansion of Itga7-positive glial cells occurs in response to muscle nerve lesion. Upon activation, muscle glial-derived progenies expressed neurotrophic genes, including Ngfr, which enables their isolation by FACS. We show that activated muscle glial cells also expressed genes potentially implicated in ECM remodeling at NMJs. Among them, we observed Tenascin C (Tnc), which was highly expressed by muscle glial cells activated upon nerve injury, and preferentially localized to NMJ. Interestingly, we observed that while the activation of muscle glial cells by acute nerve injury was reversible, upon NMJ repair. By contrast, in a mouse model of Amyotrophic Lateral Sclerosis (ALS), in which NMJ degeneration is progressive, muscle glial cells steadily increased over the course of the disease; however, they exhibited an impaired neurotrophic activity, suggesting that pathogenic activation of glial cells may be implicated in ALS progression.

Case Report: A Boy From a Consanguineous Family Diagnosed With Congenital Muscular Dystrophy Caused by Integrin Alpha 7 (ITGA7) Mutation

“…Loss of integrin α7 exacerbates a newly discovered muscle phenotype in mice lacking major adhesion complexes in skeletal muscle (Marshall et al, 2012 ). ITGA7 -expressing muscle-resident glial cells can be activated by loss of neuromuscular junction integrity (Proietti et al, 2021 ). ITGA7 -expressing muscle-resident glial cells are activated by loss of neuromuscular junction integrity, indicating α7 in late differentiation (Proietti et al, 2021 ).…”

“…ITGA7 -expressing muscle-resident glial cells can be activated by loss of neuromuscular junction integrity (Proietti et al, 2021 ). ITGA7 -expressing muscle-resident glial cells are activated by loss of neuromuscular junction integrity, indicating α7 in late differentiation (Proietti et al, 2021 ). The homozygous mutation found in our study led to a shift in the reading frame, resulting in truncating proteins with 15 miscoded amino acids ( Supplementary Figure 1 ).…”

Modelling and Refining Neuronal Circuits with Guidance Cues: Involvement of Semaphorins

“…Future studies must be directed in understanding whether ALS-related gene mutations alter homeostatic mechanisms relying on SEMA3A. Disruption of SEMAs-dependent interactions among the different cell types at the NMJ could establish a fragile premise for the irreversible degenerative process [ 115 , 116 , 137 , 138 , 139 ].…”

Spatially resolved transcriptomics reveals innervation-responsive functional clusters in skeletal muscle

“…As a consequence, the complexity of muscle tissue in pathophysiological conditions, in terms of both, cellular heterogeneity and spatial relocalization, has not yet been fully described. Despite recent advances (Lin et al, 2021; Nicoletti et al, 2020; Proietti et al, 2021), there remains an incomplete understanding regarding how traumatic events -such as nerve injury - differentially influence the specific anatomical domains and the various cellular identities in skeletal muscle. In this context, spatial transcriptomics (ST) could contribute to a revolution in the field of muscle “omics” as a fusion of recent sequencing technologies and classical histology(Achim et al, 2015; AL et al, 2020; Hunter et al, 2021; Rao et al, 2021).…”

“…Recently, due to the advent of single-cell and single-nucleus RNA sequencing (snRNAseq), the heterogeneity of muscle cellular populations and their relative role under physiological and pathological conditions such as injury, denervation or genetic disorders have begun to be methodically surveyed (Chemello et al, 2020; Dell’Orso et al, 2019; Giordani et al, 2019; Kim et al, 2020; de Micheli et al, 2020; Nicoletti et al, 2020; Petrany et al, 2020; Petrilli et al, 2017; Proietti et al, 2021; Rubenstein et al, 2020; dos Santos et al, 2020; Schaum et al, 2018) However, these approaches have several intrinsic limitations that hinder our ability to fully understand skeletal muscle pathophysiology. In particular, most of skeletal muscle mass is composed of long, polynucleated fibers, which, due to the necessary dissociation step, are incompatible with the analysis of cytoplasmic RNAs.…”