Researchers Identify Novel Genes that Regulate Muscle Stimulation and Regeneration in ALS

Researchers Identify Novel Genes that Regulate Muscle Stimulation and Regeneration in ALS
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Levels of some microRNAs (MIRs) regulating re-innervation and muscle regeneration among amyotrophic lateral sclerosis (ALS) patients, while others are lower, an Italian study has found. These molecules help distinguish slow from rapid-progression ALS, and the findings suggest that therapeutic approaches targeting these MIRs may help delay disease progression.

The study, “Potential therapeutic targets for ALS: MIR206MIR208b and MIR499 are modulated during disease progression in the skeletal muscle of patients,” appeared online in the journal Scientific Reports.

ALS is thought to be caused by an inability to repair damaged muscle cells, resulting in the loss of muscle function essential to survival, as well as muscle cell denervation, which stops muscle cells from working properly.

Prior preclinical models of ALS have suggested that the protein HDAC4 is involved in the denervation process, preventing muscle cells from being stimulated by nerves. But MIR206 can inhibit HDAC4 and boost regeneration, suggesting it could be a reasonable therapeutic strategy in ALS. MIRs are small RNA molecules that modulate the activity of some genes.

In an attempt to identify novel molecular markers of muscle resistance to denervation and atrophy, and molecules involved in muscle re-innervation during the early stages of ALS, researchers at Italy’s Università Cattolica del Sacro Cuore examined muscle samples from 14 ALS patients and 24 healthy volunteers.

Based on available clinical information, researchers divided the ALS patients into two groups: patients with slow progression, including those who had the disease for at least four years and didn’t need respiratory support, and patients with rapid progression. Then each group was divided based on the duration of the disease at muscle biopsy: early, for those diagnosed less than one year after symptom onset, and late for those diagnosed later.

Results showed that the MIR499 and MIR208B were significantly lower in the ALS rapid group than in the slow one. The authors suggest that these MIRs make skeletal muscle more resistant to denervation and the evolution of ALS.

On the other hand, MIR206 was significantly higher among late patients than early ones, with levels linked to disease progression.

The team also found that adding MIR206 to patients’ own cells grown in the lab lowered HDAC4 levels, as prior studies had suggested it would. This makes MIR206 an attractive candidate therapy for slowing the progression of ALS.

“Targeting muscular microRNAs could represent a valuable strategy aimed at restoring the molecular pathways improving motor performance and enhancing the production of growth factors (such as FGFBP1) able to facilitate the re-innervation process and delay ALS progression,” researchers stated. “Taken together, our data suggest that the molecular signalling that regulates re-innervation and muscle regeneration is hampered during the progression of skeletal muscle impairment in ALS.”

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