This
research paper was published a month ago.
Rescue of metabolic alterations in AR113Q skeletal muscle by peripheral androgen receptor gene silencing
Elisa Giorgetti,
Zhigang Yu,
Jason P. Chua,
Ryosuke Shimamura,
Lili Zhao,
Fan Zhu,
Sriram Venneti,
Maria Pennuto,
Yuanfang Guan,
Gene Hung, and
Andrew P. Lieberman1,
Highlights
•Decreased expression of carbohydrate metabolic genes characterizes AR113Q muscle
•AR113Q skeletal muscle shows decreased glycolysis and altered mitochondria
•Peripheral gene silencing by ASO rescues expression of muscle energy metabolism genes
•Altered muscle energy utilization contributes to non-neuronal disease manifestations
Summary
Spinal and bulbar muscular atrophy (SBMA), a progressive degenerative disorder, is caused by a CAG/glutamine expansion in the androgen receptor (polyQ AR). Recent studies demonstrate that skeletal muscle is an important site of toxicity that contributes to the SBMA phenotype. Here, we sought to identify critical pathways altered in muscle that underlie disease manifestations in AR113Q mice. This led to the unanticipated identification of gene expression changes affecting regulators of carbohydrate metabolism, similar to those triggered by denervation. AR113Q muscle exhibits diminished glycolysis, altered mitochondria, and an impaired response to exercise. Strikingly, the expression of genes regulating muscle energy metabolism is rescued following peripheral polyQ AR gene silencing by antisense oligonucleotides (ASO), a therapeutic strategy that alleviates disease. Our data establish the occurrence of a metabolic imbalance in SBMA muscle triggered by peripheral expression of the polyQ AR and indicate that alterations in energy utilization contribute to non-neuronal disease manifestations.
Dear Bruce,
ReplyDeleteThank you for sharing this important study.
After the bad news about BVS857 trial, I searched the literature again and I, too, found this publication. And it gave me some new hopes. Let me underline a few points in the study.
I found momentous the following sentences:
"...both type I and type II fibers were significantly reduced in size in exercised AR113Q mice, whereas WT muscle showed the opposite effect." WT means 'wild type'=healthy. So here is the reason of our common experience that our muscles need really long time to regenerate after a hard exercise: our muscles tolerate badly the overuse and we must exercise really carefully.
Another important message of the article: "These findings add to a growing appreciation of non-neuronal phenotypes in this disorder, and raise the possibility that targeting metabolic alterations may alleviate disease manifestations. In support of this hypothesis is recent work demonstrating that feeding mice a high fat diet diminishes aspects of the SBMA phenotype (Rocchi et al., 2016)." Shortly: trying the fat rich diet is a possibility, however, you have to consider your body weight as well. You have to consult your physician first, of course, but, theoretically, it may help. (As a Hungarian I am lucky because the Hungarian food is fat-rich...)
And finally the most important (IMHO): "we speculate that targeting the metabolic phenotype triggered by expression of the polyQ AR may be particularly effective in rescuing non-neuronal manifestations of the disease, including important aspects of skeletal muscle dysfunction." It gives us hope because the non-neuronal targets are easier to reach with drugs, and if you look at the successful Nusinersen-trial, they used the same gene silencing technic as in this animal experiments. I feel the solution is pretty near.
Best regards,
Istvan R.
Istvan, thanks for taking the time to add to the findings of the study. Hope for a treatment is what we live for.
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