Skeletal muscle in amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS), the major adult-onset motor neuron disease, has been viewed almost exclusively as a disease of upper and lower motor neurons, with muscle changes interpreted as a consequence of the progressive loss of motor neurons and neuromuscular junctions. This has led to the prevailing view that the involvement of muscle in ALS is only secondary to motor neuron loss. Skeletal muscle and motor neurons reciprocally influence their respective development and constitute a single functional unit. In ALS, multiple studies indicate that skeletal muscle dysfunction might contribute to progressive muscle weakness, as well as to the final demise of neuromuscular junctions and motor neurons. Furthermore, skeletal muscle has been shown to participate in disease pathogenesis of several monogenic diseases closely related to ALS. Here, we move the narrative towards a better appreciation of muscle as a contributor of disease in ALS. We review the various potential roles of skeletal muscle cells in ALS, from passive bystanders to active players in ALS pathophysiology. We also compare ALS to other motor neuron diseases and draw perspectives for future research and treatment.

Keywords: denervation; energy metabolism; mouse models; neuromuscular junction; neurophysiology.

Figure 1

Possible levels of skeletal muscle involvement in ALS. Skeletal muscle involvement in amyotrophic lateral sclerosis (ALS) is generally viewed as the secondary consequence of motor neuron (MN) death. However, muscle pathophysiology has been shown to lead to muscle autonomous defects, while also contributing to MN loss.

Figure 2

Neurophysiological and pathological alterations of ALS skeletal muscle resemble those observed in other diseases of peripheral motor nerve loss. (A) From Erminio et al.: electrical spread of compound motor action potential across leads of a multielectrode probe. Spread is more extensive with more severe disease. (B) From Telerman-Toppet and Coers: muscle biopsy sections with myosin ATPase (left), NADH diaphorase (right) showing grouping of type 1 and type 2 fibres.

Figure 3

Muscle autonomous effects. A typical muscle fibre is shown, with satellite cell (top left). Mutations in ALS-related genes such as SOD1, FUS, TARDBP or CHCHD10 (blue squares), have toxic cell autonomous effects. Satellite cells from sporadic ALS patients show decreased proliferation ability. FUS, TARDBP or SOD1 mutations affect muscle contraction through regulation of muscle gene expression, altering either muscle contraction and/or muscle differentiation. Most ALS genes also alter muscle metabolism through modifying lipid metabolism and oxidative phosphorylation (OXPHOS) (e.g. FUS, TARDBP, CHCHD10 or SOD1), while TARDBP loss affects insulin signalling. All of these events converge to impact muscle contractile function and muscle regeneration upon injury. ALS-related genes are shown in light blue squares. ALS = amyotrophic lateral sclerosis.

Figure 4

Muscle-dependent alterations in neuromuscular dialog in ALS. (A) Neuromuscular junction (NMJ) with its three major components; the terminal part of motor neuron (MN) axon (green), the subsynaptic region of myofibre (red) and the perisynaptic Schwann cell (SC). In ALS, muscles become progressively denervated, leading to compensatory muscle responses that serve to promote reinnervation of the denervated muscle fibre. Among these protective responses, growth factors (i.e. GDNF, IGF-1) and miR-206 related pathways have been shown to delay denervation. In addition, ALS mutations impact nerve-muscle dialogue at several levels. In muscle, FUS, C9ORF72 or TARDBP mutations alter expression of synaptic genes in subsynaptic nuclei, which hampers NMJ differentiation. SOD1 or sporadic ALS dampen the capacity of muscle to cluster acetylcholine receptors (AchRs) at NMJs (e.g. through rapsyn or other scaffolding proteins), and SOD1 or CHCHD10 mutations alter metabolism in mitochondria close to the NMJ. Perisynaptic Schwann cells are also affected by ALS-related mutations. ALS-related genes are shown in light blue squares. ALS = amyotrophic lateral sclerosis.