SBMA Study published regarding the AR113Q Muscle

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.

An Ode to the Androgen Receptor

I found this inspiring piece on the KDUK website this morning. Helen Devine found a way to help explain Kennedy’s Disease and the current research associated with this rare disorder.

When Research Meets Poetry

We have seen at first hand now passionate and driven the research team at UCL is. What we didn’t  Helen is at the front line in the fight against Kennedy's Disease, and to further raise awareness, she entered this poem in a Medical Research Council competition that sought creative writing from researchers that told readers '"Why does my research matter?' We at Kennedy's Disease UK were delighted that Helen was one of the 14 shortlisted finalists this year. Sadly, she didn’t win, but we feel she's a winner with this great explanation of Kennedy's Disease and the vital research she and the team are carrying out at University College London (UCL).

The Max Perutz Science Writing Award aims to encourage and recognize outstanding written communication among MRC PhD students. The annual competition challenges entrants to write an 800-word article for the general public answering tine question: 'Why does my research matter? This is Helen's fantastic entry.

An Ode to the Androgen Receptor

Neurodegenerative diseases

Occur when nerve cells die

We certainly know that it happens

But we aren't quite sure how or why

Parkinson's Disease would be easy

And Alzheimer’s or Huntington’s too

They're probably near the top of your list

If I asked you to name me a few.

But Spinal Bulbar Muscular Atrophy?

Not heard of it before?

There's something special about it,

Let me tell you a little bit more.

Weakness in the arms and legs

Make it tricky for patients to walk

Weakness in the face and tongue

Make it hard to swallow and to talk.

The faults in the Androgen Receptor

A particular genetic mutation

Male patients have the disease

Women pass it to the next generation.

When the receptor binds testosterone

The troubles really start

Patients get weakness, infertility

And problems in the heart_

The disease is slowly progressive

With no treatment and no cure

I'm hoping that might change

If I can understand it a little bit more.

So I'm going on a journey

To find out why these cells die

I am searching for the pathways

using microscopes and dyes.

The very first step is to find a way

To make a good human model

Studies from other cells and mice

May not snow the real disease problem.

Induced pluripotent stem cells

Are an exciting new innovation

Stem cells from patient skin cells

Have the androgen receptor mutation.

Motor nerves from stem cells

I grow them up in a dish

And once they are fully grown

I can study them with relish_

Stress, transport, mitochondria

Possible avenues to pursue

In the course of the research

I may find something new.

Stress is hard to deal with

In research and in a cell

I can go for a little jog

But a cell can't in a well.

So they have a special mechanism

The neat shock response its name

If this isn't working correctly

Then it may be to blame.

Axons carry the messages

One end of the cell to the other

A traffic jam in this transport

Can lead to a spot of bother,

Motor nerves are very long

So they are at great risk

If blockages and hold ups

Mean transport isn't brisk.

Mitochondria provide the energy

A cell needs to survive

If the fuel supply isn't good enough

Then the cell can start to die.

So if their shape is faulty

And they aren't working right

Tine cells start to malfunction

Pack up and say goodnight

If cell death is like a puncture

Discovering it is not enough

The next job is to fix it

And that can prove quite tough.

Motor neurons on a plate

Will be a way to screen

For a drug to reverse cell death;

That would De the dream.

SBMA is a rare disease

But patients still need a cure

I hope I can identify a good one

That's what my research is for.

The findings that I find

May also hold the key

To overall common pathways

In neurodegenerative disease.

My research is for patients with SBMA

For whom taking journeys is hard

And for whom it is a challenge
To read this poem out loud. 

Mitochondrial Dysfunction in Kennedy’s Disease

I came across the following on the Kennedy’sDisease – Raising Awareness Facebook page:

I have been taking Acetyl L-Carnitine since September and have seen a dramatic improvement in the reduction of muscle fatigue, resulting in greater activity and better health overall. I started with L-Carnitine at 500 mg to see if there were any side effects, then after one month I switched to Acetyl L-Carnitine (which crosses the blood/brain barrier), again 500mg to start then 1000. Its hard to quantify what 'better' is in our lives, but.... so far this month, I have built 12' of cabinets in the dining room, built a 15x16ft glass greenhouse at the end of the drive and moved two pallets of brick pavers and two yards of soil. All jobs that have been waiting for several years.

There was also a link to the study and I have posted that below.

First, I must qualify myself. I am not a doctor or medical student. So, any comments are strictly of a layman with an interest. In reading the article, I noticed it was not a study. This article reported the findings in studying one patient with KD. It proposes the possibility of this regiment in helping improve energy (reducing muscle fatigue). The article proposes a more complete study to determine if the initial findings can be duplicated.

When there was a lot of excitement from other Facebook members wanting to give this a try, the gentleman responded with the following caution.

Please, everyone, little steps.... no one gains if you break your leg running to the store. Try a small dose in the morning with food if you like for a few days. It is expected to help with muscle fatigue only, so that means embarking on some activity as well. The aim is to feel better; not eliminate the disease. Too much too soon and you may experience side effects that remove it as a therapeutic tool.

This is sound advice. One patient doesn’t make a study. IMPORTANT: Always consult with your primary doctor and your neurologist before beginning any supplements, especially in high dosages.

Of course, anyone with SBMA wants to know more, so I looked up the definition:

Mitochondria: Structures located in the cell's cytoplasm outside the nucleus. Mitochondria are responsible for energy production. Each consists of two sets of membranes: a smooth, continuous outer coat and an inner membrane arranged in tubules or in folds that form plate-like double membranes (cristae). The mitochrondria are the principal energy source of the cell. They not only convert nutrients into energy but also perform many other specialized tasks. Each mitochondrion has a chromosome that is made of DNA but is otherwise quite different from the better-known chromosomes in the nucleus. The mitochondrial chromosome is much smaller than other chromosomes. It is round, whereas the chromosomes in the nucleus are shaped like rods. There are many copies of the mitochondrial chromosome in every cell, whereas there is normally only one set of chromosomes in the nucleus. All mitochondrial chromosomes are inherited from the mother.

Reference: NIH, US Library of Medicine, Genetics Home Reference. Mitochondrial DNA. 

 

I also looked up possible side effects for this supplement and this is what I found at WebMid.  

Acetyl-L-carnitine is LIKELY SAFE for most adults. It can cause some side effects including stomach upset, nausea, vomiting, and restlessness. It can cause a "fishy" odor of the urine, breath, and sweat.


Under-active thyroid (hypothyroidism): There is some concern that acetyl-L-carnitine might interfere with thyroid hormone. Don’t use acetyl-L-carnitine if you have an under-active thyroid.

Seizures: An increase in the number or seriousness of seizures has been reported in people with a history of seizures who have used L-carnitine by mouth or by IV (intravenously). Since L-carnitine is related to acetyl-L-carnitine, there is a concern that this might also occur with acetyl-L-carnitine. If you have ever had a seizure, don’t take acetyl-L-carnitine.

_________________________

Mitochondrial dysfunction in Kennedy’s disease: a new pharmacological target?

Chong Wang, Wei Chen, Dan Miao, Jin-Tai Yu, and Lan Tan

Abstract

Background

Mitochondrial impairment and elevated oxidative stress have been implicated in the pathogenesis of Kennedy’s disease. However, there is still no study describing the mitochondrial nutrient management in patients with Kennedy’s disease.

Methods
We assessed the clinical and electrophysiological features in a patient with Kennedy’s disease. This patient was diagnosed by genetic analysis. We also measured the plasma 8-hydroxydeoxyguanosine (8-OHdG) levels of the patient and his family members using commercial enzyme-linked immunosorbent assay (ELISA). Treatment with intravenous L-carnitine (2 g/day) for the patient was started on admission, followed by two weeks.
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Goto this link to read the entire article

Image:  http://catalog.flatworldknowledge.com/bookhub/reader/2547?e=gob-ch20_s04