Rescuing Impaired Skeletal Muscle Function May Help Relieve Some ALS Symptoms

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Loss of normal ion flow in the skeletal muscle may worsen symptoms of amyotrophic lateral sclerosis (ALS), a mouse study shows. Researchers have identified several targets that rescue iron flow, namely chloride, in skeletal muscle, highlighting their potential in developing new therapies.

The study, “Elucidating the Contribution of Skeletal Muscle Ion Channels to Amyotrophic Lateral Sclerosis in search of new therapeutic options” was published in the journal Scientific Reports.

ALS is a progressive neurological disease that destroys nerve cells and causes disability. But the disease is known to affect other cells, including skeletal muscle tissue, leading to force decrease and muscle shrinkage (atrophy).

In both the mouse model and human patients, one of the first signs of ALS is the deterioration of signals at the neuromuscular junction (NMJ) — the site of communication between motor nerve axons and muscle fibers — even before the onset of motor neuron degeneration.

“These observations support the view that this pathology is not solely a neurological disorder, but also includes a ‘dying-back’ phenomenon, by which motor unit loss and altered muscle function precede the death of motor neurons,” researchers stated.

Muscle function is maintained by ion channels that transport ions — including chloride, sodium, potassium and calcium — and are essential for controlling muscle excitation and contraction and are important to sustain NMJ and nerve integrity.

In ALS, overexcitation of motor neurons contributes to excitotoxicity and neuron degeneration; blocking the exchange of sodium ions has been shown to help control ALS symptoms. However, the role of a chloride channel, called ClC-1, exclusively detected in skeletal muscle in ALS, remains unknown.

Researchers at the University of Bari Aldo Moro, Italy, used two animal models of ALS. One carried the mutated human SOD1 gene — the underlying cause of 15 to 20 percent of familial ALS worldwide — in all cells of the body. In the other, the mutated SOD1 gene was solely in the skeletal muscle, thereby avoiding any motor neuron involvement.

Researchers saw that, compared to normal (wild-type) animals, both animal models of ALS had  significantly reduced levels of ClC-1 protein in the tibialis anterior (TA) muscles located at the back part of the leg. RNA analysis showed that levels of protein kinase-C, an inhibitor of ClC-1 activity, were increased; those of irisin, a muscle-secreted peptide protecting brain function, decreased.

In agreement with these findings, researchers saw that the movement (conductance) of chloride ions through another leg muscle (the extensor digitorum longus muscle) was significantly reduced in both ALS models. Parallel to a decrease in the movement of chloride ions, researchers saw an increase in hyperexcitability and impaired relaxation of the muscle.

Adding chelerythrine, a selective inhibitor of protein kinase-C, to muscle fibers of either model restored chloride flow. The same was seen with another chemical compound, acetazolamide, which also increases ClC-1 channel activity. Acetazolamide works by inhibiting carbonic anhydrase, whose levels are increased in ALS patients’ motor neurons, thereby supporting acetazolamide’s potential therapeutic use.

“Additional preclinical studies are required to better assess the long-term effects of [acetazolamide]”, researchers said.

The decreased levels of irisin in both ALS mouse models supports “that its modification is an early and long-lasting event in the pathogenesis of ALS,” which supports its potential for pharmacological target.

Overall, “our results strengthen the evidence for the role of skeletal muscle in ALS pathogenesis and pave the way for the development of new therapeutic options to hamper the clinical effects of the disease,” the study concluded.