Muscle

plasticity in
response to
electrical
stimulation
-PRIYANKA. PARATE
MPTH,PUNE.
Introduction-
 Plasticityis used to describe long term changes
in how a cell/ tissue functions, although it may
also include long- term changes in the
appearance of the cell/ tissue.

 Muscle plasticity is defined as the ability of a

given muscle to alter its structural and functional
properties in accordance with the environmental
conditions imposed on it.

 Chronic electrical stimulation provides one of the

‘cleanest’ views of muscle adaptation to
increased use.
 This model has been used by basic scientists to
study skeletal muscle adaptation since it induces a
repeatable, quantifiable amount of exercise.

 Thus it is been able to synthesize a collection of

such studies in a manner that provides a fairly global
view of muscle structural and physiological changes
that occur in response to stimulation.

 It is known that muscles which perform different

tasks, in addition to having different muscle
architecture, respond to different electrical input.
 Foreg, sketelal muscles that play a postural role, and
thus have a high proportion of slow fibers, are
physiologically activated at low frequencies.

 Conversely, muscles with a very high proportion of

fast fibers may be activated only intermittently with
high frequency bursts of electrical activity.

 Thefact that electrical activity and muscle properties

seem to be interrelated, provides an experimental
basis for understanding muscle plasticity.
 The best documented effects of electrical stimulation on
skeletal muscles are those that occur after chronic, low
frequency stimulation (similar to the activity of a ‘slow’
muscles is imposed upon a predominantly ‘fast’ muscle).

 Ifthe stimulator is activated at a nominal frequency of

about 10hz and allowed to operate 8-24hours per day, a
well defined progression of changes is observed whereby
the fast muscles first changes its metabolic and then its
contractile properties to completely ‘transform’ into a
‘slow’ muscle.
 Based on time series studies fiber biochemistry that
the changes that occur result from a true
transformation of a single fast fibre into a slow fiber
and not from selective loss of fast fibers, but with
subsequent slow fiber regeneration or proliferation.

 The fast fibers actually become slow fibers. Infact,

even the physical appearance of the stimulated
muscles approaches that of the more postural
muscles by taking on a ‘deep red’ appearance.
 TIME COURSE OF MUSCLE
FIBER TRANSFORMATION
 2-12 Days.

 Increases are measured in the volume percent of

mitochondria, oxidative enzyme activity, number of
capillaries per square millimeter, total blood flow, and
total oxygen consumption, reflecting a profoundly
increased muscle metabolic activity.

 Theincrease in oxidative enzymes and capillary

density are manifested functionally as a decrease in
muscle fatigability.
FIGURE-1
 Figure -1- Left- increase in size and number of
mitochondria( denoted by arrows in normal panel)
present in the tissue as a result of the chronic
stimulation.

 Right- Histochemically, metabolic alterations are

reflected as an increased percentage of FOG fibers
at the expense of FG fibers (represented as’ darkly’
staining in the stimulated SDH stain) Also, note the
increase in the capillaries.
FIGURE-2
 After 14 days, the Z- band begins to increase in width ,
and a decrease in the amount and activity of calcium
ATPase is observed.

 Figure-2-left- At this point, the width of the Z -band

(shown here as a brown band) begins to increase
towards the wider value observed for normal slow
muscle. The significance of Z disk width change is not
known.

 Right- The amount and activity of the calcium transport

ATPase (shown in red) decreases and changes its
particle distribution within the Sarcoplasmic Reticulum
bilayer.
FIGURE-3
 FIGURE-3-The Z- band is the full width of a
normal slow contracting muscle and the
density of T system has decreased.
 At this point, the transformed fast contracting
muscle is indistinguishable from a normal
slow contracting muscle.
 Here is an important point: just because activity
increases, does not mean that all muscle proteins
must also increase.

 Some proteins increase in amount(i.e. are up

regulated) and others decrease in amount (i.e are
down regulated). The choice which the muscle
makes depends on the goal of the adaptation.

 Asthe muscle is receiving information consistent with

being chronically active at fairly low levels, it alters
genetic expression pattern to create a structure
consistent with this functional requirement.
 We conclude two things from this typical time course
of transformation:

 Muscle metabolic enzymes, capillaries, SR, T-system

are much more easily changed than contractile
proteins.

 Chronic stimulation increases muscle endurance

capacity, but is not an effective means for increasing
fiber size in normal muscle.
 The decrease in skeletal muscle mass and fiber area
should not be viewed as an atrophic or degenerative
response. i.e, an undesirable ‘overuse’ type of injury.

 Rather, it appears that fiber atrophy represents a

deliberate adaptive response of muscle fiber to chronic
stimulation – perhaps to decrease diffusion distances
from the muscle fiber to the interstitial spaces which
contain the capillaries.

 Itis interesting that chronic low frequency electrical

stimulation is the best way to make a muscle ‘weaker’.
 HIERARCHY OF MOTOR UNIT RECRUITMENT AND
MUSCLE FIBER DIVERSITY
 Henneman’s size principle states that under load,
motor units are recruited from smallest to largest.

 In practice, this means that slow-twitch, low-force,

fatigue-resistant muscle fibers are activated before
fast-twitch, high-force, less fatigue-resistant muscle
fibers.

 During movements, different motor units are recruited

sequentially and in a strict, hierarchical order. CLFS,
however, activates all motor units synchronously, thus
by passing this physiological order of recruitment.
 Normally, force is produced by recruiting the smallest
motor units first; with increasing effort to produce
more force, the larger units join in.

 The largest motor units are rarely used and are

recruited only during maximal effort for brief periods of
time.

 It is this hierarchy of motor unit recruitment order that

might in part be responsible for the heterogeneity of
muscle fibers within the same muscle, particularly
since muscle fibers belonging to the same motor unit,
although not identical, are similar.
 Thus, muscle fiber heterogeneity is a consequence
of motor unit diversity. This organization indicates
the influence of motor neuron activity upon muscle
fiber phenotypes.
 COMPARISON OF STIMULATION-INDUCED
ACTIVITY TO EXERCISE

 Electrical stimulation has made a fundamental

contribution to the understanding of the influence of
motor neuron activity on muscle fiber phenotypes.

 Muscle activity induced by electrical stimulation is, in

many respects, unnatural. Two major differences exist
between voluntary and reflexly elicited contractions.

 First, during normal movement, motor units are

activated asynchronously, whereas electrical
stimulation causes synchronous activity of all motor
units.
 Second, the hierarchical order of recruitment is
cancelled by supramaximal electrical stimulation, and
the largest, normally least active units are stimulated
simultaneously with other, usually more active, motor
units.

 Thus, it is the normally inactive motor units that

experience the most profound change in their use
when the muscle is electrically stimulated.

 In spite of these differences between normal and

electrically induced activity, imposed electrical activity
has certain advantages compared to exercise or other
protocols increasing muscle activity.
 First, the rigid hierarchical order of motor unit recruitment,
just discussed, is bypassed. In fact, electrical stimulation
reverses the order of recruitment, because, due to the
high excitability of large axons, large motor units are
activated at low current intensity.

 As a consequence, all motor units (i.e., even those

normally not recruited in exercise) can be simultaneously
activated by the same pattern of activity.

 Second, the standardized regimen of electrical stimulation

offers the possibility to investigate adaptive responses to
well-defined and reproducible patterns of activation.
 Third, electrical stimulation can attain much higher
levels of activity over time than any exercise regimen
and, therefore, the adaptive potential of the system is
challenged to its limits.

 Fourth, enhanced activity is restricted to the target

muscle and is likely to have few, if any, secondary
systemic effects.

 And finally, high levels of activity can be imposed on

the target muscle by electrical stimulation from the
beginning, because the central nervous,
cardiovascular, and other systems will not interfere
with and limit the amount of activity, as is the case in
exercise.
 Taken together, the use of electrical stimulation makes
it possible to follow the time-course of activity-induced
changes under standardized conditions and to
determine the full adaptive potential of muscle fibers, as
well as its limits.
 CHRONIC LOW-FREQUENCY STIMULATION
 Effects of indirect electrical stimulation by implanted
electrodes make use of tonic, slow frequency patterns
of activation that convert the phenotype of fast-twitch
muscles toward that of slower muscles.

 In addition to the already mentioned points, there are

other advantages to this experimental design:

 1. Without interfering with the innervation and the

natural activity delivered by the nerve, muscle fibers
can be activated by entirely novel impulse patterns.
 2. It is unlikely that a tonic pattern will activate sensory
nerve fibers, which may cause pain.

 3. It is less likely that neuromuscular transmission will

be blocked by a low-frequency stimulus pattern, as
compared to a high-frequency protocol.

 The transformation of a slow muscle toward a faster

contracting muscle can also be achieved by electrical
stimulation, but only when its physiological tonic
activity is removed by manipulations, such as
denervation or application of tetrodotoxin (TTX) to the
nerve.
 The pattern of stimulation used to transform a
denervated slow-twitch muscle into a faster muscle
resembles that, normally delivered by the motor nerve
to a fast-twitch muscle, namely intermittent trains of
high-frequency activity.
 CHANGES INDUCED BY CHRONIC LOW-FREQUENCY
STIMULATION
 Theearliest studies also revealed that CLFS in the
rabbit leads to a reduction in muscle bulk and tetanic
tension.

 Thisloss in muscle bulk is due to a reduction of fiber

diameter of the largest most fatigable muscle fibers
that are exposed to sudden excessive activity.

 Mostof the initial observations were obtained from

chronically stimulated rabbit extensor digitorum longus
(EDL) and tibialis anterior (TA) muscles.
 After long-term stimulation, two main functional
changes were observed: slowing of the time-courses of
contraction and relaxation; and increased fatigue
resistance.

 Many of the functional changes of the stimulated

muscle reflect profound alterations in gene expression
leading to a transformation of the muscle fibers
phenotype.

 Studies on rabbit and rat have shown that this includes

most proteins of the myofibrillar apparatus, proteins of
the sarcoplasmic reticulum and cytosol-regulating
Ca2+ dynamics, and enzyme proteins mediating
 anaerobic- and aerobic-oxidative pathways of energy
supply and energy-rich phosphate transfer.

 Adaptive changes furthermore include membrane-

associated proteins, such as sensing and signal-
transducing proteins of excitation– contraction (EC)
coupling, glucose and fatty acid transport, as well as
lactate exchange.

 Proteinscharacteristic of the synaptic specialization of

fast-and slow-twitch muscles, such as acetylcholine
esterase-1, are also affected.

 Oxygen and fuel supply, and removal of metabolites

 and ions related to enhanced activity, are facilitated by
an expansion of the extracellular space, increased
capillary density, perfusion, and myoglobin content.

 Also,increases in satellite cell content have recently

been demonstrated with low-frequency stimulation of
rat muscle.

 The major changes at the sarcomere level encompass

the replacement of fast by slow protein isoforms.

 Inthe thick filament, there is an exchange of myosin

heavy-chain (MHC) isoforms that, according to time-
course studies, proceeds in an orderly fashion.
 The sequence of the transitions in MHC isoform
expression follows an order that seems to be related to
gradual differences in the energy cost of force
production and different ATP phosphorylation potentials
of fast and slow fiber types.

 The major changes of the thin filament were observed in

the regulatory tropomyosin–troponin complex. They
consist of a shift from fast to slow isoforms, and these
changes are synchronous with those in MHC isoforms.

 In addition to the alterations in the thick and thin

filament, CLFS also affects the structure and
composition of the Z-disk. During the fast-to-slow
 conversion of the fiber, there is an increase in the
thickness of the Z-disk and a change of its a-actinin
isoform pattern so that these come to resemble those of
a slow-twitch fiber.

 Increases in intermediate filament proteins occur in

parallel with the remodeling of the Z-disk and most
likely lead to a strengthening of the force-bearing
structures of the muscle fiber.

 This metabolic rearrangement is also reflected by a

pronounced increase in mitochondrial volume density.
Further studies have provided more details with
regard to the time-course of changes in enzyme
activities, isozyme patterns, and species-specific
responses.
 Interestingly,glucose transporter GLUT4 and
hexokinase, both playing key roles in glucose transport
and glucose activation, increase rapidly after the onset
of CLFS.

 The content of another membrane-associated enzyme,

Na+,K+–ATPase, has also been shown to increase in
fast-twitch muscle exposed to CLFS.
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