The Impact of Neurological Disorders on Intramuscular Connective Tissue

Abstract Neurological disorders (peripheral and central) produce motor impairments that are not fully explained by neural lesions and following muscle fiber adaptations. This study aimed to investigate the impact of peripheral and central neurological disorders on intramuscular connective tissue via unilateral lower limb peripheral nerve injury rat model, an scoping review, as well as a mouse middle cerebral artery occlusion (MCAO) model. In study 1, the rat model of unilateral sciatic nerve injury, extracellular matrix (ECM) changes in the gastrocnemius and thoracolumbar fascia (TLF) was evaluated. Six weeks post-injury, HA was reduced, and collagen accumulated not only in the denervated limb but also contralaterally and in the TLF, paralleling motor deficits. These findings indicate a systemic ECM response to peripheral nerve injury that increases tissue stiffness and may predispose to secondary musculoskeletal problems proximal to the lesion. In study 2, a scoping review (PRISMA-ScR; ROBINS-E) synthesized evidence on IMCT alterations in hypertonic muscles due to central neurological disorders. Across twelve studies, increased collagen and glycosaminoglycan content, fascia thickening, fibroblast changes, and altered IMCT structure were consistently reported; collagen content correlated positively with spasticity and stiffness. Most data derived from chronic stages, underscoring the need for longitudinal, mechanistic studies. In study 3, using a mouse middle cerebral artery occlusion (MCAO) model, ECM remodeling in forelimb muscles four weeks post-stroke was evaluated. Unlike peripheral injury, HA increased bilaterally while collagen levels did not significantly change, pointing to a distinct, systemic HA-dominant remodeling pattern after central lesions that may elevate tissue viscosity and contribute to post-stroke hypertonia. In summary, these studies reveal convergent yet lesion-specific ECM phenotypes: peripheral injury—HA reduction and collagen accumulation; central injury—HA accumulation with stable collagen, both expressed systemically across limbs and fascia. This work positions ECM-targeted strategies, alongside neural repair, as plausible avenues to mitigate muscle hypertonia and improve functional recovery after neurological injury.