Newswise — A combination approach of increasing the SIRT3 protein and inhibiting PARPs (poly-ADP ribose polymerase) helps rescue motor endurance of mice modeling the neuromuscular disease spinal bulbar and muscular atrophy (SBMA), also known as Kennedy’s disease, according to a new study by Philadelphia College of Osteopathic Medicine (PCOM) researchers.
SBMA is an adult-onset genetic disorder that affects men due to a mutation in the androgen receptor gene, making the protein form a long glutamine expansion (polyglutamine) that is toxic to motor neurons and skeletal muscle. Men suffer with progressive difficulty walking, speaking and swallowing, usually resulting in the need for mobility aides, and potentially feeding and respiratory support as they age. There is no cure or disease-modifying therapy available at this time, so SBMA research seeks to identify ways to improve muscle function for these patients.
The study, published in iScience, was led by Heather L. Montie, PhD, an associate professor of Neuroscience, Physiology and Pharmacology at PCOM, and the primary author is David Garcia Castro, DO, PhD ’23, now an anesthesiology resident at Yale. The study first examined how activating or increasing SIRT3—a protein in the sirtuin family that regulates mitochondrial and metabolic function—could reduce oxidative stress and death of cells modeling SBMA. This approach looked promising in cell models, but it wasn’t nearly as effective in mice, though overexpressing the SIRT3 protein resulted in a trend in motor recovery, as well as a correction of a metabolic pathway involved in energy production known as the TCA cycle.
From there, the research team sought to boost blunted SIRT3 activity by giving it more of its diminished molecular fuel, NAD+, (an acronym to describe a molecule that’s critical to proper cell function). The team found that mice modeling SBMA have very low levels of SIRT3 protein, and its molecular fuel, NAD+, is also severely diminished. That means that, even in cells that were given more SIRT3, “it was not able to work as well as it should,” Montie said, due to the low fuel source.
Since NAD+ is diminished in SBMA but critical to SIRT3 activity and overall metabolism, the team focused on restoring NAD+ in mice modeling SBMA. That’s where PARPs, proteins that aid in repairing damaged DNA, came into the study. When PARPs are active they use up a lot of NAD+, and they could have potentially contributed to the low NAD+ in the SBMA mice.
Although the researchers found that inhibition of PARPs did not rescue reduced NAD+ in the skeletal muscle of mice modeling SBMA, increasing SIRT3 and inhibiting PARPs fully restored hexokinase, the initial enzyme of glycolysis, which is a cellular pathway critical for energy production. This combination treatment rescued exercise endurance of the mice modeling SBMA.
This combination approach that targets the metabolic anomalies in SBMA restored motor function “downstream” of the disease-causing protein, polyglutamine-expanded (mutant) androgen receptor. That means the toxic, disease-initiating proteins still exist, but the mess they make—disruption of “multiple cellular processes, including mitochondrial function, metabolism, and energy production,” according to the authors—could be fixed up enough to reduce the burden of disease.
“As researchers develop strategies to reduce the toxic protein, perhaps we could layer on treatments like this to further boost the restoration of muscle function,” Montie said. “It’s exciting that we can make an effective change without targeting that toxic protein.”
In the study, the mice treated with increased SIRT3 and PARP inhibition doubled the time they spent running on a treadmill, illustrating that muscle endurance—more than other measures, such as grip strength—significantly improved. That effect points back to the importance of metabolism, which is severely disrupted in SBMA, and its critical role in maintenance of muscle function.
The work was supported by PCOM’s Division of Research and Center for Chronic Disorders of Aging, the Guinta Family Research Scholarship, and the United States Department of Agriculture.
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