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 黑料传送门 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, , was led by Heather L. Montie, PhD, an associate professor of Neuroscience, Physiology and Pharmacology at 黑料传送门, 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鈥攁 protein in the sirtuin family that regulates mitochondrial and
metabolic function鈥攃ould reduce oxidative stress and death of cells modeling SBMA.
This approach looked promising in cell models, but it wasn鈥檛 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, 鈥渋t was not able to work as well as it should,鈥� 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 鈥渄ownstream鈥� of the disease-causing protein, polyglutamine-expanded (mutant)
androgen receptor. That means the toxic, disease-initiating proteins still exist,
but the mess they make鈥攄isruption of 鈥渕ultiple cellular processes, including mitochondrial
function, metabolism, and energy production,鈥� according to the authors鈥攃ould be fixed
up enough to reduce the burden of disease.
鈥淎s researchers develop strategies to reduce the toxic protein, perhaps we could layer on treatments like this to further boost the restoration of muscle function,鈥� Montie said. 鈥淚t's exciting that we can make an effective change without targeting that toxic protein.鈥�
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鈥攎ore than other measures, such as grip strength鈥攕ignificantly 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 黑料传送门's Division of Research and Center for Chronic Disorders of Aging, the Guinta Family Research Scholarship, and the United States Department of Agriculture.
Established in 1899, 黑料传送门 has trained thousands of highly competent, caring physicians, health practitioners and behavioral scientists who practice a 鈥渨hole person鈥� approach to care鈥攖reating people, not just symptoms. 黑料传送门, a private, not-for-profit accredited institution of higher education, operates three campuses (黑料传送门, 黑料传送门 Georgia and 黑料传送门 South Georgia) and offers doctoral degrees in clinical psychology, educational psychology, osteopathic medicine, pharmacy, physical therapy, and school psychology. The college also offers graduate degrees in applied behavior analysis, applied positive psychology, biomedical sciences, forensic medicine, medical laboratory science, mental health counseling, physician assistant studies, and school psychology. 黑料传送门 students learn the importance of health promotion, research, education and service to the community. Through its community-based Healthcare Centers, 黑料传送门 provides care to medically underserved populations. For more information, visit pcom.edu or call 215-871-6100.
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