Liver issues precede neuromuscular symptoms in SMA: Mouse study
Understanding process 'crucial' to better treat patients, per researchers
Metabolic abnormalities, including the buildup of fat in the liver and other issues, occur before the loss of motor neurons, according to a study in a mouse model of spinal muscular atrophy (SMA).
The mice, with reduced levels of the SMN protein, exhibited decreased levels of glucose (sugar) in the blood, indicative of disrupted glucose metabolism, and abnormalities in cells in the pancreas.
The researchers say these findings shed light on the underlying disease processes in SMA and could ultimately help lead to better treatments for patients.
“It is crucial to understand the impact of individual tissues on the overall picture of the disease to treat patients as effectively as possible,” the team wrote, noting that, “with the increasing use of therapeutics, SMA patients’ lives are being extended and peripheral symptoms are becoming more apparent.”
The study, “Peripheral defects precede neuromuscular pathology in the Smn2B/− mouse model of spinal muscular atrophy,” was published in the Journal of Neuromuscular Diseases.
Investigating links between SMN protein and liver issues
SMA is caused mainly by mutations in the SMN1 gene, which disrupt the production of the SMN protein. This results in symptoms such as progressive muscle weakness and atrophy, or wasting. In the absence of the SMN protein, specialized nerve cells that control movement, known as motor neurons, begin to degenerate.
However, there is increasing evidence that the lack of the SMN protein affects more than motor neurons, as the protein is normally found in cells throughout the body.
The bodywide loss of the protein may negatively impact other non-neurological organs, with evidence from a mouse model indicating alterations in the liver, digestive tract, and pancreas.
“Interestingly, therapeutic strategies are more effective when delivered systemically instead of directly to the central nervous system,” composed of the brain and spinal cord, the scientists wrote, noting this is “likely due to the contributions of peripheral organs to SMA disease.”
But “while it is becoming clear that the depletion of SMN affects several systems within the body, the relationship between the affected systems and their impact on the overall development of disease in SMA is not well understood,” the team wrote.
In particular, fatty liver disease — a condition marked by the buildup of fat in the liver, causing inflammation and damage — may be a common complication of SMA. Underscoring the relevant role of the liver in SMA, a study in a mouse model found that gene therapy that specifically delivers the SMN1 gene to the liver restored muscle size and increased the number of insulin-producing cells in the pancreas.
In this study, a team led by researchers from the Ottawa Hospital Research Institute in Canada used a mouse model of SMA that shows degeneration of motor neurons from early in life and a severe SMA presentation that includes immune defects, gastrointestinal dysfunction, fatty liver, and pancreatic issues.
“We characterized several neuronal and non-neuronal defects in the [SMA mouse model] throughout development to better understand the progression of the disease and the relationship between tissue defects,” the researchers wrote.
Liver affected ‘early’ in mouse model of SMA, researchers find
Overall, the mice survived for a median of 22 days, with their first symptom — decreased weight gain — emerging at 11 days after birth. Elevated levels of neurofilament light chain protein, a biomarker of nerve damage, were noted on the same day.
At 13 days after birth, the researchers found a buildup of fat in the liver, known as liver steatosis. These liver issues preceded muscular wasting, which occurred 17 days after the mice were born, as well as the degeneration of motor neurons, first noticed two days later. Nerve loss at the neuromuscular junction, the site where muscles and nerves connect, was noted at day 17 after birth.
“The liver is therefore affected early in the [mouse] model, prior to neuromuscular pathology [disease],” the researchers wrote.
We have displayed that the liver may be an early target of SMA, with the potential to impact several other systems affected in the disease. The liver performs an important role … that should not be overlooked in the care and treatment of SMA patients.
At 15 days after birth, the animals showed other non-neuronal abnormalities, specifically decreased levels of blood glucose relative to their healthy littermates; those animals served as controls.
Four days later, the researchers found changes in the cellular composition of the pancreas of mutant mice, with a disruption in the ratio of alpha cells, which produce a hormone called glucagon. That raises blood sugar to beta cells, which produce insulin that lowers blood sugar. This pancreatic damage coincided in time with the loss of motor neurons.
“We have displayed that the liver may be an early target of SMA, with the potential to impact several other systems affected in the disease. The liver performs an important role in neuronal [nerve cell] development, metabolism, and detoxification that should not be overlooked in the care and treatment of SMA patients,” the scientists wrote.
“A holistic treatment strategy will provide the greatest outcome for patients,” the team added.
According to the scientists, their work in mice “has provided an in-depth systematic characterization of [this mouse model’s characteristics] to allow for a better understanding of the connections between the systems affected in SMA and to guide future research.”
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