Skeletal Muscle Satellite Cells, Mitochondria, and MicroRNAs: Their Involvement in the Pathogenesis of ALS

Abstract

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a fatal motor neuron disorder. It results in progressive degeneration and death of upper and lower motor neurons, protein aggregation, severe muscle atrophy and respiratory insufficiency. Median survival with ALS is between 2 and 5 years from the onset of symptoms. ALS manifests as either familial ALS (FALS) (~10% of cases) or sporadic ALS (SALS), (~90% of cases). Mutations in the copper/zinc (CuZn) superoxide dismutase (SOD1) gene account for ~20% of FALS cases and the mutant SOD1 mouse model has been used extensively to help understand the ALS pathology. As the precise mechanisms causing ALS are not well understood there is presently no cure. Recent evidence suggests that motor neuron degradation may involve a cell non-autonomous phenomenon involving numerous cell types within various tissues. Skeletal muscle is now considered as an important tissue involved in the pathogenesis of ALS by activating a retrograde signaling cascade that degrades motor neurons. Skeletal muscle heath and function are regulated by numerous factors including satellite cells, mitochondria and microRNAs. Studies demonstrate that in ALS these factors show various levels of dysregulation within the skeletal muscle. This review provides an overview of their dysregulation in various ALS models as well as how they may contribute individually and/or synergistically to the ALS pathogenesis.

Keywords: amyotrophic lateral sclerosis; miRNA; mitochondria; neuromuscular junction; satellite cell; skeletal muscle.

Figure 1

Potential crosstalk between SC, mitochondria and miRNAs to influence NMJ and skeletal muscle health in ALS. Green arrows indicate regulatory relationships between molecules, as well as between molecules and structures. A reduction in Pax7 and MyoD may contribute to the attenuation in SC activation and number. SCs not only maintain skeletal muscle fiber size and function, but those located near the NMJ also play role in maintaining NMJ stability. Similarly, downregulation of molecular targets including PGC-1α, ERRα, and NRF may impair mitochondrial biogenesis and function. As mitochondria play role in maintaining calcium homeostasis and muscle repair, their dysregulation may also contribute to skeletal muscle and NMJ deterioration. Perturbations in miRNAs, such as miR-206, may negatively impact regenerative capacity and NMJ stability via their control over MRFs (myogenic regulatory factors) and HDAC4 transcription. Additionally, the upregulation of miRNA-23a may negatively impact the PGC-1α signaling cascade and mitochondrial function; as consequence indirectly contributing to impaired skeletal muscle repair and NMJ stability.