Download Comparison Between Animal and Human Studies of Skeletal

Comparison Between Animal and Human
Studies of Skeletal Muscle Adaptation
to Chronic Stimulation
RICHARD L. LIEBER,PH.D.*
phy,12-15,30,35 preliminary studies promoting
the use of FES to regain muscle function lost
after upper motor neuron lesion have been
heralded.32,33,36*37
Additionally, FES has been
reported to reduce postoperative rehabilitation time,3,1Z*’4
aid in the correction of flexion c o n t r a c t u r e ~ and
, ~ ~ ~improve
~
or augment muscle f ~ n c t i o n . ~ * ~However,
~-”
because the physiologic basis of FES has yet to
be elucidated, there is no general agreement
on stimulation parameters, stimulation
doses, or stimulation conditions.
In contrast to the recent emergence of FES
as a clinical tool, chronic electrical stimulation has long been used to study skeletal
muscle adaptation because it induces a repeatable, quantifiable amount of “exercise.”
The best documented effects of electrical
stimulation on skeletal muscle are those observed following chronic, low frequency
electrical stimulation of “fast” skeletal muscle using implanted electrode systems. In this
setting, a well-defined progression of muscular changes is observed that enables investigation of the mechanism and time course of
muscle adaptation to chronic stimulation. In
basic studies, however, the stimulation time
is extraordinary ( 12-24 hours/day) compared with that usually possible in the clinics,
the electrode systems are usually implanted,
and the experimental subjects are stimulated
during normal cage activity.
What can be learned from these basic
Functional electrical stimulation (FES) has recently emerged as a clinical tool for treatment of
neuromuscular disorders.Chronic muscle stimulation, however, has long been used by basic scientists studying the details of the muscular adaptation process. Biochemical, morphological, and
functional changes occur in skeletal muscle secondary to chronic stimulation. Chronic stimulation (12-24 hours per day for six weeks) results in
a well-defined progression of changes in which a
“fast” muscle becomes a typical “slow” muscle
with a large decrease in force-generating capacity.
On the other hand, clinical studies of FES have
demonstrated muscle strengthening following
treatment. An attempt is made to reconcile the
results obtained in the two fields.
It has been demonstrated under a variety
of conditions that skeletal muscle adapts to
As a
the level of use imposed upon it.23,38343
result of this plasticity, the use of functional
electrical stimulation (FES) to strengthen
skeletal muscle was originally proposed. Several studies suggested that FES might decrease or delay the effects of disuse atro* Assistant Professor of Surgery, Division of Orthopaedics and Rehabilitation, Department of Surgery, Veterans Administration Medical Center and University of
California, San Diego, California.
Supported by the Veterans Administration, the Mentor Corporation (Minneapolis, Minnesota), Empi, Inc.
(Fridley, Minnesota), and USPHS grant R23-AM35 192.
Reprint requests to Richard L. Lieber, Ph.D., Division
of Orthopaedics and Rehabilitation, Department of
Surgery, V- I5 1, Veterans Administration Medical
Center, San Diego, CA 92 161.
Received: December 29, 1987.
19
20
Clinical Orthopaedics
Lieber
and Related Research
If low frequency stimulation is applied 24
hours per day, the total transformation process requires only about 30 days. The earliest
observed changes occur within a few hours
after the onset of stimulation when the sarcoplasmic reticulum (SR) begins to swell."
Within the next two to 12 days, increases are
measured in the volume percent of mitochondria, oxidative enzyme activity, the
number of capillaries per square millimeter,
total blood flow, and total oxygen consump
tion, thus reflecting the increased metabolic
activity of the musc1e.4~10~18~20~40
Histochemically, this is reflected in an increased percentage of Type 2A or fast-oxidative-glycolytic
ANIMAL STUDIES OF CHRONIC
(FOG) fibers at the expense of Type 2B or
MUSCLE STIMULATION
fast-glycolytic (FG) fibers.I8zz9At this point,
the width of the Z-band begins to increase
The best documented effects of electrical
toward the wider value observed for normal
stimulation on skeletal muscle are those that
slow muscle." The amount and activity of
occur after chronic, low-frequency stimulathe calcium transport ATPase decrease and
tion of a predominantly "fast" muscle durchange the particle distribution within the
ing normal cage activity. In this setting, a
SR bilayer.
This decrease in the
well-defined progression of changes is obamount and activity of the calcium ATPase
served in which the muscle first changes its
can be detected physiologically as a prometabolic and then its contractile properties
longed time-to-peak twitch tension and a
to become a "slow" muscle.43This has been
prolonged relaxation time of a muscle
documented in the rabbit tibialis anterior
* ' ~ ,increase
~~
in oxidative enand extensor digitorum longus,'7-20,24.39,- t w i t c h . l ~ ~ The
40.44-47 the rat extensor digitorum l ~ n g u s , ~ . zymes
~ ~ and capillary density is manifested as
a decrease in muscle fatigability.19736*44Fithe cat intertran~verse,~'
and the cat peroneus longus and flexor digitorum longus,'g9 nally, after about four weeks of continuous
stimulation, an alteration in the myosin light
therefore the effects observed are probably
not species- or muscle-specific. The fast-to- chain profile is observed whereby the normally fast muscle, containing only light
slow transformation that occurs is detectable
by measurement of muscle ~ontractile,',~,~.-chains LClf, LC2f, and LC3f, now contains
light chains characteristic of slow fibers, i.e.,
ultrastructural,
hi stochemica1,4,5,18,29.47 biochemical,5,I7,20,24,39,40,44,46,47
LCls and LC2s.19*39*46
By this time, muscle
and morphologica14~5~'8~40
properties. In all
fiber cross-sectional area, maximum tetanic
tension, and muscle weight have decreased
cases, following transformation the new slow
fibers are completely indistinguishable from
s i g n i f i ~ a n t l y . ~ .The
~ . ' ~ Z-band
-~~
is now the
normal slow skeletal muscle fibers. It is also
full width of that normally observed in a slow
clear, based on time-series studiesI0.'I and
fiber, and the density of the T-system is
greatly decreased." The muscle is now indissingle-fiber b i ~ c h e m i s t r y , ~that
~ . ~ ~the
tinguishable from a normal slow skeletal
changes that occur result from transfomation at the level of the single fiber and not
muscle in every respect.
from fast-fiber degeneration with subsequent
A number of conclusions can be formed
slow-fiber regeneration.
based on this well-established time-course of
science studies and applied to the clinical
practice of FES? While it is clear that chronic
muscle stimulation using implanted electrodes alters skeletal muscle properties in a
well-defined manner, it is still not clear
whether this treatment modality, when applied in a clinically relevant manner, actually
strengthens muscle or otherwise improves its
condition. This paper briefly reviews the
basic science literature on muscle stimulation to suggest muscular changes that might
be induced by clinical application of FES.
Portions of this review were contained in an
earlier series on muscle adaptation.26
17924,29344,47
9*44945
0*24540
Number 233
August, 1988
transformation: (1) muscle metabolic enzymes, capillaries, SR, and T-system are
much more easily altered than contractile
proteins and (2) while chronic stimulation
does increase muscle endurance capacity, it
is .not an effective means for strengthening
normal muscle. In fact, most studies report a
5070-8070 decrease in tetanic tension following chronic stimulation. The effect of stimulation on denervated or tenotomized muscle
is much more promising in terms of its clinical applicability. Several weeks of denervation decreases muscle weight and maximum
tetanic tension by 30%-40%. Stimulation of
muscle following denervation attenuates the
decrease in weight and maximum tetanic
tension so that the net loss may only be
10%-20%.~~*~~~~
MIJscle Properties After Chronic Stimulation
21
As in animal studies, transcutaneous FES
increases muscle oxidative capacity as evidenced by an increased histochemical succinate dehydrogenase staining intensity33and
decreased muscle fatigabilit~.~~
An increase
in the passive range of motion has also been
observed.’ Interestingly, cases demonstrating
increased voluntary motor function secondary to FES treatment (or traditional physical
therapy) are mentioned in the l i t e r a t ~ r e ~ . ~ ~
although the basis for these observations remains to be elucidated.
COMPARISON BETWEEN ANIMAL
AND HUMAN STUDIES
An apparent contradiction exists between
animal and human studies. Why do most
human studies generally demonstrate muscle
HUMAN STUDIES OF CHRONIC
strengthening with FES while basic studies
MUSCLE STIMULATION
show weakening and/or fiber type transformation? The three major differences between most animal and human studies preThe best studied effects of FES in humans
sented to date are that (1) chronic animal
are those obtained by isometric stimulation
FES is usually accomplished using implanted
of quadriceps muscles at about 30” of flexelectrode systems while most human muscle
ion. The treatment usually consists of relais stimulated transcutaneously (cf: Refertively high frequency stimulation (37-2000
ences 33 and 36); (2) the stimulation doses in
Hz) for less than one hour per day for five to
animal studies have been ten to 100 times
28 weeks. Muscle forces reached during the
greater than the doses used in human studies;
treatment periods are reported to be equal to
and (3) human muscle has been stimulated
50%-100% of a subject’s maximum volunisometrically while animal limbs were altary contraction (MVC). Following the treatment period, joint tOrqUe,7,13-16,22,’5,30-32,36,42
lowed to move freely.
First, the difference is probably not related
joint range of
and muscle fiber
to the implantation of electrodes. It has been
have been measured.
shown that because motor nerves have a
Electrical stimulation training in humans
lower threshold to activation than muscle
results in a moderate amount of muscle
fibers during electrical activation of a whole
strengthening relative to immobilization or
muscle, the nerves are first depolarized causinactivity, but no increase relative to voluning depolarization of the muscle fibers.21If a
tary contraction or normal activity. Electrisubject is curarized (thus blocking neurocal stimulation superimposed upon volunmuscular transmission), activation threshtary contraction does not strengthen muscle
more than either treatment a l ~ n e . ’ * ~In~the
* ~ ’ olds for muscle contraction increase by an
order of magnitude. One study has demoncase of severely atrophic muscle (as with
strated no difference in muscle histochemical
denervated animal muscle), muscle strength
appearance after chronic stimulation with eiis clearly increased by transcutaneous FES.
22
Clinical Orthopedics
and Related Research
Lieber
ther transcutaneous or implanted elect r o d e ~ . Second,
~'
increased stimulation dose
causes decreased muscle force in basic studies; therefore, that human stimulation doses
are much lower than animal doses is probably not responsible for the different degrees
of strengthening noted. The difference probably lies in the conditions of stimulation (ie.,
isometric vs. free moving). Muscle strengthening depends, to a large degree, on the stress
imposed on the muscle. Sprinting exercise,
in which fibers are allowed to shorten upon
full activation, results in less strengthening
than weight-lifting, in which the fibers remain more nearly isometric or even contract
eccentrically.' The change in maximum
force that occurs as a function of shortening
velocity is given by the classic force-velocity
equation. For example, if a muscle is stimulated isometrically at 10 Hz, the force developed is equivalent to about 30% of its maximum tetanic tension (Po).Now, if the same
muscle is allowed to shorten at a velocity
equal to only 10%of its maximum shortening velocity (easily obtainable under physiologic conditions), the force developed is only
about 18% Po. Thus, to the extent that muscle stress results in muscle strengthening, the
stimulating conditions will influence the results of electrical stimulation training.
In order to reconcile the disparity of animal and human research on FES, future research in FES application to muscle rehabilitation requires an examination of the physiological basis for the muscular response to
transcutaneous stimulation. In order to utilize the available literature on muscle plasticity, experiments must be designed such that
direct muscle treatment force is well-defined.
Experimental parameters measured must be
related to muscle force generating capacity
(e.g., isometric torque, muscle fiber diameters) and not simply muscle bulk (e.g.,limb
volume or circumference). In order to make
valid comparisons with the basic science literature, it may be necessary to distinguish
between FES treatment of fast and slow normal or atrophied muscle under well-defined
conditions. As a result of such studies, FES
may be applied to a variety of clinical problems, with underlying fundamental work
available to justify the various procedures.
ACKNOWLEDGMENTS
The author gratefully acknowledges the excellent
technical assistance of Thalia McKee-Woodburn, Dr.
Thomas D. Ferro, Dr. Marcia K. Beckman, and Dr.
Michael Mai.
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