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From: Kofi on 9 Apr 2008 00:16
Given the interaction of p75 with ASIC3, a receptor upregulated by
acetyl-l-carnitine, I think this new result explains how ALCAR provides
clinical relief for chronic fatigue sufferers (it's a shame ALCAR sends
hair into catagen through the same receptor and also alters cancer risks
the same way; perhaps ASIC3 will provide a more specific pharmaceutical
target).

<http://www.sciencedaily.com/releases/2008/04/080407153037.htm>

Biological Link Between Pain And Fatigue Discovered

ScienceDaily (Apr. 9, 2008) � A recent University of Iowa study reveals
a biological link between pain and fatigue and may help explain why more
women than men are diagnosed with chronic pain and fatigue conditions
like fibromyalgia and chronic fatigue syndrome.

Working with mice, the researchers, led by Kathleen Sluka, Ph.D.,
professor in the Graduate Program in Physical Therapy and Rehabilitation
Science in the UI Roy J. and Lucille A. Carver College of Medicine,
found that a protein involved in muscle pain works in conjunction with
the male hormone testosterone to protect against muscle fatigue.

Chronic pain and fatigue often occur together -- as many as three in
four people with chronic, widespread musculoskeletal pain report having
fatigue; and as many as 94 percent of people with chronic fatigue
syndromes report muscle pain. Women make up the majority of patients
with these conditions.

To probe the link between pain and fatigue, and the influence of sex,
the UI team compared exercise-induced muscle fatigue in male and female
mice with and without ASIC3 -- an acid-activated ion channel protein
that the team has shown to be involved in musculoskeletal pain.

A task involving three one-hour runs produced different levels of
fatigue in the different groups of mice as measured by the temporary
loss of muscle strength caused by the exercise.

Male mice with ASIC3 were less fatigued by the task than female mice.
However, male mice without the ASIC3 protein showed levels of fatigue
that were similar to the female mice and were greater than for the
normal males.

In addition, when female mice with ASIC3 were given testosterone, their
muscles became as resistant to fatigue as the normal male mice. In
contrast, the muscle strength of female mice without the protein was not
boosted by testosterone.

"The differences in fatigue between males and females depends on both
the presence of testosterone and the activation of ASIC3 channels, which
suggests that they are interacting somehow to protect against fatigue,"
Sluka said. "These differences may help explain some of the underlying
differences we see in chronic pain conditions that include fatigue with
respect to the predominance of women over men."

The study, which was published in the Feb. 28 issue of the American
Journal of Physiology -- Regulatory, Integrative and Comparative
Physiology, indicates that muscle pain and fatigue are not independent
conditions and may share a common pathway that is disrupted in chronic
muscle pain conditions. The team plans to continue their studies and
investigate whether pain enhances fatigue more in females than males.

"Our long-term goal is to come up with better treatments for chronic
musculoskeletal pain," Sluka said. "But the fatigue that is typically
associated with chronic, widespread pain is also a big clinical problem
-- it leaves people unable to work or engage in social activities. If we
could find a way to reduce fatigue, we could really improve quality of
life for these patients."

In addition to Sluka, the UI research team included Lynn Burnes, a
research assistant and lead author of the study; Sandra Kolker; Jing
Danielson; and Roxanne Walder. The study was funded in part by grants
from the National Institute of Arthritis and Musculoskeletal and Skin
Diseases.

Adapted from materials provided by University of Iowa.

Pain. 2008 Mar 13; [Epub ahead of print] Related Articles, LinkOut
�
Role of ASIC3 in the primary and secondary hyperalgesia produced by
joint inflammation in mice.

Ikeuchi M, Kolker SJ, Burnes LA, Walder RY, Sluka KA.
Physical Therapy and Rehabilitation Science Graduate Program, Pain
Research Program, University of Iowa, Iowa City, IA 52242, USA.

The acid sensing ion channel 3 (ASIC3) is critical for the development
of secondary hyperalgesia as measured by mechanical stimulation of the
paw following muscle insult. We designed experiments to test whether
ASIC3 was necessary for the development of both primary and secondary
mechanical hyperalgesia that develops after joint inflammation. We used
ASIC3 -/- mice and examined the primary (response to tweezers) and
secondary hyperalgesia (von-Frey filaments) that develops after joint
inflammation comparing to ASIC3 +/+ mice. We also examined the
localization of ASIC3 to the knee joint afferents innervating the
synovium using immunohistochemical techniques before and after joint
inflammation. We show that secondary mechanical hyperalgesia does not
develop in ASIC3 -/- mice. However, the primary mechanical hyperalgesia
of the inflamed knee joint still develops in ASIC3 -/- mice and is
similar to ASIC3 +/+ mice. In knee joint synovium from ASIC3 +/+ mice
without joint inflammation, ASIC3 was not localized to joint afferents
that were stained with an antibody to protein gene product (PGP) 9.5 or
calcitonin gene-related peptide (CGRP). ASIC3 was found, however, in
synoviocytes of the knee joint of uninflamed mice. In ASIC3 +/+ mice
with joint inflammation, ASIC3 co-localized with PGP 9.5 or CGRP in
joint afferents innervating the synovium. We conclude that the decreased
pH that occurs after inflammation would activate ASIC3 on primary
afferent fibers innervating the knee joint, increasing the input to the
spinal cord resulting in central sensitization manifested behaviorally
as secondary hyperalgesia of the paw.

PMID: 18343037

Am J Physiol Regul Integr Comp Physiol. 2008 Apr;294(4):R1347-55. Epub
2008 Feb 27.
�
Enhanced muscle fatigue occurs in male but not female ASIC3-/- mice.
Burnes LA, Kolker SJ, Danielson JF, Walder RY, Sluka KA.

Graduate Program in Physical Therapy and Rehabilitation Science, 1-242
MEB, Univ. of Iowa, Iowa City, IA 52242.).

Muscle fatigue is associated with a number of clinical diseases,
including chronic pain conditions. Decreases in extracellular pH
activates acid-sensing ion channel 3 (ASIC3), depolarizes muscle,
protects against fatigue, and produces pain. We examined whether
ASIC3-/- mice were more fatigable than ASIC3+/+ mice in a task-dependent
manner. We developed two exercise protocols to measure exercise-induced
muscle fatigue: (fatigue task 1, three 1-h runs; fatigue task 2, three
30-min runs). In fatigue task 1, male ASIC3+/+ mice muscle showed less
fatigue than male ASIC3-/- mice and female ASIC3+/+ mice. No differences
in fatigue were observed in fatigue task 2. We then tested whether the
development of muscle fatigue was dependent on sex and modulated by
testosterone. Female ASIC3+/+ mice that were ovariectomized and
administered testosterone developed less muscle fatigue than female
ASIC3+/+ mice and behaved similarly to male ASIC3+/+ mice. However,
testosterone was unable to rescue the muscle fatigue responses in
ovariectomized ASIC3-/- mice. Plasma levels of testosterone from male
ASIC3-/- mice were significantly lower than in male ASIC3+/+ mice and
were similar to female ASIC3+/+ mice. Muscle fiber types, measured by
counting ATPase-stained whole muscle sections, were similar in calf
muscles from male and female ASIC3+/+ mice. These data suggest that both
ASIC3 and testosterone are necessary to protect against muscle fatigue
in a task-dependent manner. Also, differences in expression of ASIC3 and
the development of exercise-induced fatigue could explain the female
predominance in clinical syndromes of pain that include muscle fatigue.

PMID: 18305024

J Bone Miner Res. 2007 Dec;22(12):1996-2006.
�
Expression of acid-sensing ion channel 3 (ASIC3) in nucleus pulposus
cells of the intervertebral disc is regulated by p75NTR and ERK
signaling.

Uchiyama Y, Cheng CC, Danielson KG, Mochida J, Albert TJ, Shapiro IM,
Risbud MV.
Department of Orthopaedic Surgery, Thomas Jefferson University,
Philadelphia, PA 19107, USA.

Although a recent study has shown that skeletal tissues express ASICs,
their function is unknown. We show that intervertebral disc cells
express ASIC3; moreover, expression is uniquely regulated and needed for
survival in a low pH and hypoeromsotic medium. These findings suggest
that ASIC3 may adapt disc cells to their hydrodynamically stressed
microenvironment. INTRODUCTION: The nucleus pulposus is an avascular,
hydrated tissue that permits the intervertebral disc to resist
compressive loads to the spine. Because the tissue is hyperosmotic and
avascular, the pH of the nucleus pulposus is low. To determine the
mechanisms by which the disc cells accommodate to the low pH and
hypertonicity, the expression and regulation of the acid sensing ion
channel (ASIC)3 was examined. MATERIALS AND METHODS: Expression of ASICs
in cells of the intervertebral disc was analyzed. To study its
regulation, we cloned the 2.8-kb rat ASIC3 promoter and performed
luciferase reporter assays. The effect of pharmacological inhibition of
ASICs on disc cell survival was studied by measuring MTT and caspase-3
activities. RESULTS: ASIC3 was expressed in discal tissues and cultured
disc cells in vitro. Because studies of neuronal cells have shown that
ASIC3 expression and promoter activity is induced by nerve growth factor
(NGF), we examined the effect of NGF on nucleus pulposus cells.
Surprisingly, ASIC3 promoter activity did not increase after NGF
treatment. The absence of induction was linked to nonexpression of
tropomyosin-related kinase A (TrkA), a high-affinity NGF receptor,
although a modest expression of p75NTR was seen. When treated with
p75NTR antibody or transfected with dominant negative-p75NTR plasmid,
there was significant suppression of ASIC3 basal promoter activity. To
further explore the downstream mechanism of control of ASIC3 basal
promoter activity, we blocked p75NTR and measured phospho extracellular
matrix regulated kinase (pERK) levels. We found that DN-p75NTR
suppressed NGF mediated transient ERK activation. Moreover, inhibition
of ERK activity by dominant negative-mitogen activated protein kinase
kinase (DN-MEK) resulted in a dose-dependent suppression of ASIC3 basal
promoter activity, whereas overexpression of constitutively active MEK1
caused an increase in ASIC3 promoter activity. Finally, to gain insight
in the functional importance of ASIC3, we suppressed ASIC activity in
nucleus pulposus cells. Noteworthy, under both hyperosmotic and acidic
conditions, ASIC3 served to promote cell survival and lower the activity
of the pro-apoptosis protein, caspase-3. CONCLUSIONS: Results of this
study indicate that NGF serves to maintain the basal expression of ASIC3
through p75NTR and ERK signaling in discal cells. We suggest that ASIC3
is needed for adaptation of the nucleus pulposus and annulus fibrosus
cells to the acidic and hyperosmotic microenvironment of the
intervertebral disc.

Publication Types:
* Research Support, N.I.H., Extramural

PMID: 17696763
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