During denervation induced muscle atrophy, the loss of neuro-muscular junction (NMJ) integrity and the consequent cessation of nerve signal transmission to muscle, lead to a decline in myofiber size mass and contractile activity. However, the identity of the cell types implicated in the muscle response to nerve injury has not been clearly defined. Here, we describe a subpopulation of muscle resident glial cells activated by loss of NMJ integrity. Gene expression analysis at bulk and single cell level revealed the existence of a population of Itga7-expressing cells, which are distinct from muscle satellite cells and are selectively activated upon nerve injury. Upon nerve lesion, these cells expanded and activated a neurotrophic gene program, including the expression of a prospective selection marker - Ngfr - and a number of neurotrophic genes as well as ECM components. Among them, we observed that Tenascin C (Tnc) was specifically produced by muscle glial cells activated by nerve injury and preferentially localized to NMJ. Activation of muscle-resident glial cells by nerve injury induced a neurotrophic phenotype, which was reversible upon recovery of NMJ integrity; by contrast, muscle-resident glial cells in skeletal muscles of a mouse model of Amyotrophic Lateral Sclerosis (ALS) steadily increased over the course of the disease and exhibited an impaired neurotrophic activity, suggesting that pathogenic activation of glial cells may be implicated in ALS progression.