Skeletal muscle in motor neuron diseases: therapeutic target and delivery route for potential treatments

Abstract

Lower motor neuron (LMN) degeneration occurs in several diseases that affect patients from neonates to elderly and can either be genetically transmitted or occur sporadically. Among diseases involving LMN degeneration, spinal muscular atrophy (SMA) and spinal bulbar muscular atrophy (Kennedy's disease, SBMA) are pure genetic diseases linked to loss of the SMN gene (SMA) or expansion of a polyglutamine tract in the androgen receptor gene (SBMA) while amyotrophic lateral sclerosis (ALS) can either be of genetic origin or occur sporadically. In this review, our aim is to put forward the hypothesis that muscle fiber atrophy and weakness might not be a simple collateral damage of LMN degeneration, but instead that muscle fibers may be the site of crucial pathogenic events in these diseases. In SMA, the SMN gene was shown to be required for muscle structure and strength as well as for neuromuscular junction formation, and a subset of SMA patients develop myopathic pathology. In SBMA, the occurrence of myopathic histopathology in patients and animal models, along with neuromuscular phenotype of animal models expressing the androgen receptor in muscle only has lead to the proposal that SBMA may indeed be a muscle disease. Lastly, in ALS, at least part of the phenotype might be explained by pathogenic events occuring in skeletal muscle. Apart from its potential pathogenic role, skeletal muscle pathophysiological events might be a target for treatments and/or be a preferential route for targeting motor neurons.

Figure 1. electrophysiological and muscle pathological features of LMN degeneration in skeletal muscle

A. Electrophysiological (EMG) recording of a patient with ALS demonstrating fibrillation potentials at rest, i.e. spontaneous denervation-related muscle activity. B–D. Muscle biopsy of a patient with ALS. All the features associated with neurogenic disorders, i.e. grouping of atrophic fibers (B,C), predominance of one type of fiber (D), and presence of angulated fibers (D), are observed. (B: semi-thin section, X 250; C: H–E staining, X 200; D: NADH-TR staining, X 100).

Figure 2. potential mechanisms involving skeletal muscle in SMA

Loss of SMN1 leads to two consequences in skeletal muscle. First, SMN1 loss leads to abnormalities in sarcomere structure, which are a likely cause of muscle weakness. Second, SMN1 loss decreases the potential of muscle to produce mature AchR subunits, leading to an abnormal development of NMJs. SMN1 loss in motor neurons has also profound effects on NMJ development. See text (section 3) for further details.

Figure 3. potential mechanisms involving skeletal muscle in SBMA

The mutant AR toxicity is unmasked by testosterone. This leads to myopathic features, such as myotonic discharges and elevation of blood CK, contributing to muscle weakness and letality. On the other hand, mutant AR toxicity (or wild type AR overexpression) dismantles NMJs through yet unknown mechanisms. A pathogenic function of mutant AR in motor neurons has also been documented. See text (section 4) for further details.

Figure 4. potential mechanisms involving skeletal muscle in SOD1-linked ALS

Mutant SOD1 expression in skeletal muscle leads to oxidative stress, muscle atrophy and weakness. mSOD1 mice skeletal muscles are also hypermetabolic but whether mSOD1 expression in muscle or in other cell types is responsible of this phenotype is unknown. Muscle hypermetabolism is sufficient to drive NMJ destruction and systemic energy deficit. mSOD1 expression in both motor neurons and glial cells is also involved in the overall ALS phenotype of mSOD1 mice. See text (section 5) for further details.

Figure 5. targeting skeletal muscle in LMN degeneration

A potential therapeutic treatment for LMN degeneration might target deleterious processes occuring in muscle itself.

Figure 6. skeletal muscle as a delivery route in LMN degeneration

Skeletal muscle is also a privilegied route to deliver drugs targeting motor neurons through retrograde transport.