Cholesterol-lowering drugs and the effect on muscle repair and regeneration

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Cholesterol-lowering drugs and the effect on muscle repair and

regeneration

http://www.eurekalert.org/pub_releases/2008-09/aps-cda092308.php

Statins are powerful drugs that reduce " bad " cholesterol and thus cut

the risk of a heart attack. While these medications offer tremendous

benefits to millions, they can carry side effects for some. The most

frequently reported consequence is fatigue, and about nine percent of

patients report statin-related pain. Both can be exacerbated when

statin doses are increased, or physical activity is added. The

results of a new study may offer another note of caution for high-

dose statin patients. Working with primary human satellite cell

cultures, researchers have found that statins at higher doses may

affect the ability of the skeletal muscles–which allow the body to

move–to repair and regenerate themselves.

The study is entitled " Simvastatin Reduces Human Primary Satellite

Cell Proliferation in Culture. " It was conducted by Thalacker-

Mercer, Baker, Calderon and Marcas Bamman, University

of Alabama at Birmingham. They will discuss their findings at the

American Physiological Society (APS; www.The-APS.org) conference, The

Integrative Biology of Exercise V. The meeting is being held

September 24-27, 2008 in Hilton Head, SC.

The Study

Statins have been reported to have adverse effects on skeletal muscle

in both human and animal models causing cramping and fatigue and

potentially myopathy. Relatively little is known regarding the effect

of statins on the muscle progenitor cells (i.e., satellite cells

(SC)) which play a key role in skeletal muscle repair and

regeneration following exercise or injury. SC remain in a quiescent

state until stimulated to proliferate. Statins are known to have

antiproliferative effects in other cell types and therefore may

inhibit or effect this critical step in muscle repair. Thus it is

important to understand the influence of statins on SC function which

may further affect the overall health and physiology of human

skeletal muscle..

The study examined the proliferative capacity of human satellite

cells in culture, which were exposed, to a lipophilic statin:

simvastatin. The aim of the study was to determine SC viability

during proliferation when treated with statins which may be

indicative of the ability of SCs to undergo mitosis (i.e. divide to

make new cells).

The research team used primary cell lines isolated from quadriceps

muscle biopsies. SC were mixed and grown for 48 hours with several

concentrations of statin: 0.0, 0 plus the solvent DMSO (control),

0.05, 0.1, 1.0, 10, or 100µM. The MTS assay was utilized to measure

cell viability/reproducibility.

Additionally the investigators determined the effects of varying

concentrations of simvastatin on SCs in different states (i.e.,

undergoing differentiation or differentiated into myotubes).

Key Findings

The researchers found the following:

There was a dose dependent decrease in the viability of the satellite

cells at 1.0, 10 and 100µM concentrations of simvastatin. At

approximately 5.0 µM concentration the viability of the proliferating

cells was reduced by 50% (equivalent to the availability of

simvastatin in circulation from a 40 milligram dose per day used in

some patients). Specifically, the higher end concentrations led to

reduced SC proliferation, which would likely negatively affect the

muscle's ability to heal and/or repair itself.

There was no change in the viability of satellite cells at

concentrations of 0.05 or 0.1µM.

Cell viability was reduced by approximately half in differentiating

cells and myotubes with concentrations of 1.0 and 5.0 µM,

respectively.

Next Steps

According to Dr. Thalacker-Mercer, a member of the research

team, " While these are preliminary data and more research is

necessary, the results indicate serious adverse effects of statins

that may alter the ability of skeletal muscle to repair and

regenerate due to the anti-proliferative effects of statins. "

Looking ahead, she added, " We are very interested in these effects in

the older population. It is possible that older adults may not be

able to distinguish between muscle pain related to a statin effect or

an effect of aging and therefore adverse effects of statins in older

adults may be under-reported. Therefore, our next step is to examine

statins among older adults. "