Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that leads to progressive degeneration of motor neurons (MNs) and severe muscle atrophy without effective treatment. Most research on ALS has been focused on the study of MNs and supporting cells of the central nervous system. Strikingly, the recent observations of pathological changes in muscle occurring before disease onset and independent from MN degeneration have bolstered the interest for the study of muscle tissue as a potential target for delivery of therapies for ALS. Skeletal muscle has just been described as a tissue with an important secretory function that is toxic to MNs in the context of ALS. Moreover, a fine-tuning balance between biosynthetic and atrophic pathways is necessary to induce myogenesis for muscle tissue repair. Compromising this response due to primary metabolic abnormalities in the muscle could trigger defective muscle regeneration and neuromuscular junction restoration, with deleterious consequences for MNs and thereby hastening the development of ALS. However, it remains puzzling how backward signaling from the muscle could impinge on MN death. This review provides a comprehensive analysis on the current state-of-the-art of the role of the skeletal muscle in ALS, highlighting its contribution to the neurodegeneration in ALS through backward-signaling processes as a newly uncovered mechanism for a peripheral etiopathogenesis of the disease.
Highlights
Licensee MDPI, Basel, Switzerland.Neuromuscular diseases involve the injury or dysfunction of peripheral nerves and muscles [1]
Amyotrophic lateral sclerosis (ALS) is characterized by progressive degeneration of motor neurons (MN) in the brain and the spinal cord, which control the contraction of muscles that enable moving, speaking, breathing, and swallowing
This section discusses the relevance of metabolic and nutritional support provided by glia cell types to MNs and how tipping the homeostasis of these cells could affect MN
Summary
The recent growing number of clinical and animal/cellular studies provides unclouded evidence that MN damage could arise from non-cell autonomous mechanisms displayed by glia [12] or muscle cells [13] In this line, growing molecular evidence supports the fact that MN diseases can occur following distal axonal degeneration, supporting the “dying back” hypothesis, implying that pathological changes appear in the axon distally, at the NMJ or even in the skeletal muscle, and are transmitted into the soma prior to the onset of clinical symptoms and MN death [14,15]. Tackling the skeletal muscle as a direct target in ALS disease could accelerate potential advances in future therapeutic interventions
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