LDL Cholesterol - Missing Link for Neuromuscular Communication


Another link in explaining the effect of statin drugs on various neurodegenerative diseases was recently identified. In seeking an explanation for the effect of statin drugs to trigger certain neuromuscular diseases such as myasthenia gravis and amyotrophic lateral sclerosis, scientists have identified a likely candidate in the form of a lipoprotein known as Lrp4.

Previous studies demonstrated that a specific molecule on the surface of the muscle fiber, called MuSK, is critical in relaying instructions from motor neurons. Likewise, previous studies showed that a molecule called Agrin is the instruction from these nerve cells. The missing link in the field has been how Agrin 'talks' to MuSK. It is Lrp4 that makes this communication possible.

That this protein is a type of low density lipoprotein offers a possible explanation for the occurrence of certain neuromuscular diseases after statin treatment has begun. As reductase inhibitors, statin drugs were designed to block the mevalonate pathway of cholesterol synthesis. The effect of a statin is to inhibit the synthesis of cholesterol, thereby possibly interfering with Lrp4 availability preventing normal communication between nerves and muscles.  

Researchers at the NYU Langone Medical Center have found that a protein named Lrp4 is the missing link that allows communication between two crucial molecules-one derived from the nerve and the other from muscle-that enables the formation of the synapse. Our ability to move and breathe depends upon the special connection between nerve cells and skeletal muscle fibers - the 'neuromuscular synapse,'" explains Dr. Steven J. Burden, principle investigator for this discovery.   

Ralph Edwards, medical director of Vigibase, The World Health Organization adverse drug reaction monitoring center, announced to the world last year the reality of excess amyotrophic lateral sclerosis in statin users worldwide. This caused a flurry of excitement at Medwatch, the FDA's adverse drug monitoring center, that claimed to be unaware of this trend. Yet my own small repository had, in the previous year, received some 45 reports of ALS associated with statins prompting me to undertake a survey with the People's Pharmacy readership, identifying some 200 additional cases, unreported to Medwatch because no one suspected a possible relationship.

These new cases all were forwarded to Medwatch. Although I have examined other mechanisms that might explain the relationship of statin drugs to ALS-like symptoms, this Lrp4 discovery is particularly appealing. Nerve conduction studies are fundamentally sound since nerve fibers are intact all the way to Agrin. And even muscle responsiveness to direct electrical stimulation is preserved but muscles remain functionless to the usual endogenous stimuli.
         
Making a neuromuscular synapse requires many steps. Once motor axons find the muscle fiber, they must instruct the muscle to organize 'molecular antennae' consisting of receptors for the neurotransmitter acetylcholine, which is released from nerve cells and stimulates muscle contraction. Deficiencies in any of these steps are responsible for multiple diseases that impair movement. Work by many groups, both basic science and clinical, over several decades, has been dedicated to understanding the instructions, which pass between nerve cells and muscle fibers, that are essential to both form and maintain neuromuscular synapses.
         
A number of studies recently has reported on the role of cholesterol in cell communication via glycoprotein synthesis formerly thought to be exclusively the role of dolichols but now known to involve cholesterol as well. The complex role of cholesterol was completely unrecognized until statin associated side effects prompted further research.. This discovery of a cholesterol-like biomolecule vital for linking muscle to nerve fiber helps greatly to explain the vexing problem of apparent excessive neurodegenerative problems associated with statin use and is but another glaring example of insufficient background research before the statin class of drugs was marketed.

Duane Graveline MD MPH
Former USAF Flight Surgeon
Former NASA Astronaut
Retired Family Doctor
 

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