Upregulation of Sarcolemmal Hemichannels and Inflammatory Transcripts with Neuromuscular Junction Instability during Lower Limb Unloading in Humans

Abstract

Human skeletal muscle atrophy and a disproportionate force loss occur within a few days of unloading in space and on Earth, but the underlying mechanisms are not fully understood. Disruption of neuromuscular junction homeostasis has been proposed as one of the possible causes. Here, we investigated the potential mechanisms involved in this neuromuscular disruption induced by a 10-day unilateral lower limb suspension (ULLS) in humans. Specifically, we investigated hemichannels’ upregulation, neuromuscular junction and axonal damage, neurotrophins’ receptor downregulation and inflammatory transcriptional signatures. Biomarkers were evaluated at local and systemic levels. At the sarcolemmal level, changes were found to be associated with an increased expression of connexin 43 and pannexin-1. Upregulation of the inflammatory transcripts revealed by deep transcriptomics was found after 10 days of ULLS. The destabilisation of the neuromuscular junction was not accompanied by changes in the secretion of the brain-derived neurotrophic factor and neurotrophin-4, while their receptor, BDNF/NT growth factors receptor (TrkB), decreased. Furthermore, at 5 days of ULLS, there was already a significant upregulation of the serum neurofilament light chain concentration, an established clinical biomarker of axonal injury. At 10 days of ULLS, other biomarkers of early denervation processes appeared. Hence, short periods of muscle unloading induce sarcolemmal hemichannels upregulation, inflammatory transcripts upregulation, neuromuscular junction instability and axonal damage.

Resveratrol, a Multitasking Molecule That Improves Skeletal Muscle Health

“…The NMJ is the point of communication between the motor neuron and the skeletal muscle cell, and it is the site for the transmission of action potential to activate contraction. The integrity of the NMJ is perturbed in neuromuscular disorders and in skeletal muscle aging and disuse [20,[28][29][30], with a consequent loss of its organization, fragmentation and degeneration, contributing to reduced muscle performance. Already in 2006, Lagouge and collaborators [7], based on the evidence that RES improved the motor coordination and traction force in mice fed on a high-fat diet, suggested that RES could modulate neuromuscular communication.…”