Muscle Evolution and Fiber Types
Vincent J. Caiozzo and Kenneth M. Baldwin
Contents
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
Types of Motor Units, Muscle Fiber Types, and Design Constraints . . . . . . . . . . . . . . .
Motor Units and Muscle Fiber Types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
What Sets the Theoretical Boundary of Muscle Performance? . . . . . . . . . . . . . . . . . . . . . . . . . .
What Are the Primary Design Constraints of Muscle Performance? . . . . . . . . . . . . . . . . . . . .
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4
The Impact of Microgravity on Design Constraints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Animal Models to Induce Skeletal Muscle Atrophy and Functional Deficits . . . . . . . . . . . 5
Human Models to Induce Skeletal Muscle Atrophy and Functional Deficits . . . . . . . . . . . 10
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Abstract
Muscle wasting commonly occurs in space.
The absence of gravity degrades key physiological properties of skeletal muscle. Animal
and human models are helpful in understanding associated mechanisms of deconditioning
and muscle atrophy.
V. J. Caiozzo (*)
Departments of Physiology and Biophysics and
Orthopedics, University of California, Irvine, CA, USA
The Institute for Clinical and Translational Sciences,
School of Medicine, University of California, Irvine, CA,
USA
e-mail: vjcaiozz@uci.edu
K. M. Baldwin
Departments of Physiology and Biophysics and
Orthopedics, University of California, Irvine, CA, USA
e-mail: kmbaldwi@uci.edu
Overview
Space is the most extreme environment known to
humans. The vacuum and temperature of space
are life-threatening challenges, and, as such,
spacecraft are designed with basically an Earthlike environment. There are other environmental
challenges associated with spaceflight such as
exposure to space radiation and the absence of
gravity. Neither of these factors is immediately
life-threatening but has the potential to profoundly degrade both the physiology and health
of astronauts. With respect to gravity, it clearly
played a role in human evolution, especially with
respect to the physiological properties of the musculoskeletal and cardiovascular systems, and it is
well known that its absence produces marked
physiological deconditioning. This is especially
evident with respect to skeletal muscle, where
relatively short periods of muscle unloading
© Springer Nature Switzerland AG 2020
L. R. Young, J. P. Sutton (eds.), Handbook of Bioastronautics,
https://doi.org/10.1007/978-3-319-10152-1_21-2
1
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produce substantial losses in muscle mass and
function. The challenge is to use short-term exposure to microgravity as a test-bed for understanding the most vulnerable physiological systems and
to implement effective countermeasures that can
ultimately be used for moderate (Mars) and longduration (Mars +) space exploration.
Given this background, the focus is to address
fundamental issues with respect to microgravity
and how the absence of gravity degrades key
physiological properties of skeletal muscle. Our
view is based around three critical considerations.
The first of these is that the boundary of muscle
performance is defined by the force-velocity
relationship and that the absence of gravity can
substantially constrain this boundary. Second, the
physiology of muscle is determined primarily by
three different components: (i) the motor, which is
represented by the presence of sarcomeres and
their arrangement into myofibrils; (ii) the on-off
switch, represented by the sarcoplasmic reticulum (SR); and (iii) the mitochondria, which
serves as the power source needed to sustain the
ATP demands of the myofibrils and SR. These
three components typically occupy approximately
90% of a skeletal muscle fiber’s volume (Alway
et al. 1988; Ferretti et al. 1997) and, as such,
dictate the primary physiological properties of a
given muscle fiber. Finally, we will advocate that
the study of muscle atrophy (loss of crosssectional area) process needs to move beyond
just a sarcomere-centric phenomenon to one that
views the sarcomere, mitochondria, and SR as a
single ultrastructural unit (hereby referred to as a
SMART unit: Sarcomere, MitochondriA, and sarcoplasmic ReTiculum) that is proportionately
disassembled as a result of altered physiological
conditions such as reduced muscle loading as
occurs in microgravity. In viewing the muscle
atrophy process in a more global fashion, the
field of muscle plasticity needs to move toward
developing a Unified Muscle Atrophy Model
(UMAM) that not only seeks to understand the
disassembly of each individual component of the
SMART unit but also examines the impact of
muscle unloading on key scaffold/tethering proteins thought to be responsible for the
V. J. Caiozzo and K. M. Baldwin
organizational arrangement of the sarcomere,
mitochondria, and SR into a single functional
unit and how such units are disassembled in
such a coordinated fashion.
Types of Motor Units, Muscle Fiber
Types, and Design Constraints
Motor Units and Muscle Fiber Types
The musculoskeletal system is the largest organ
system across the entire subphylum of vertebrates,
including humans. This system is designed for
enabling locomotion and other movement patterns including the important role of opposing
gravity. From a global perspective, the performance of skeletal muscle is determined by (i) the
recruitment pattern of motor units; (ii) the ability
of the cardiorespiratory system to support the
metabolic demand of a skeletal muscle; (iii) the
cross-sectional area and length of a given muscle;
and (iv) the capacity of an individual skeletal
muscle fiber to produce force under a wide array
of contractile conditions that vary with respect to
velocity, cycling rates, duty cycle, and duration.
At the global level, factors i–iii above might be
considered extrinsic factors, while the properties
of an individual skeletal muscle fiber that determines any aspect of factor iv would be considered
intrinsic factors.
Motor units (a motor neuron and the pool/population of muscle fibers it controls; see Fig. 1)
have classically been categorized into three distinct types/groups (although there is probably
greater heterogeneity than just three types) and
classically defined as (i) slow (S), (ii) fast-fatigue
resistant (FR), and (iii) fast-fatigable (FF). Key
extrinsic factors such as motor neuron cell body
size and sensory feedback play a fundamental role
in determining the recruitment order such that S
motor units are the first recruited by the nervous
system when opposing gravity and in performing
low-intensity activities such as jogging. These
motor units are the most fatigue resistant. When
the exercise intensity is elevated (e.g., highintensity running, cycling, etc.), the FR motor
Muscle Evolution and Fiber Types
units also are recruited. Generally, the FF motor
units are brought into play primarily when powerful movements are performed such as lifting
heavy weights or performing highly ballistic
movements such as a slam dunk in basketball
(certainly one of the most extreme examples of
humans working against gravity). One way to
think about this recruitment process is that motor
units are recruited as a function of the degree of
mechanical force needed while performing a
given type of physical activity.
The intrinsic properties of skeletal muscle
fibers vary with respect to the type of motor unit.
The muscle fibers found in S-type motor units are
typically described as slow type I or slow oxidative (SO) fibers. These fibers have slow maximal
shortening velocities that result from the expression of the slow type I myosin heavy chain
(MHC) isoform. Their rate of relaxation is limited
by a slow-type calcium ATPase pump, which then
constrains the frequency at which the muscle fiber
can undergo cyclic phases of contractionrelaxation. Slow type I fibers have the highest
mitochondrial density (oxidative metabolism)
but lowest glycolytic capacity (glycogen mobilization enzymes).
3
The muscle fibers found in FR motor units are
commonly referred to as fast type IIA or fast
oxidative-glycolytic (FOG) muscle fibers. Some
critical intrinsic factors that shape the physiological properties of these fibers are as follows. First,
they contain a faster type of myosin heavy chain
isoform (i.e., fast type IIA MHC), which allows
this type of muscle fiber to produce shortening
velocities greater than that of the slow type I
fibers. Second, these fibers have a fast form of
the calcium-ATPase pump providing these fibers
with the ability to undergo higher cycling rates
than that of slow type I/SO fibers. Finally, from a
metabolic perspective, fast type IIA fibers have a
relatively high glycolytic capacity and a moderate
oxidative capacity (see Fig. 1).
The FF motor units control a pool of muscle
fibers referred to as fast type IIX or fast glycolytic
(FG) fibers. These fibers have the greatest maximal shortening velocity due to the presence of the
fast type IIX MHC isoform, and they are capable
of achieving high Ca++ cycling rates. Their metabolic profile is characterized by the lowest mitochondrial content but the greatest glycolytic
capacity (see Fig. 1).
Fig. 1 Overall organization of motor units and some key properties of muscle fibers found in each type of motor unit
4
What Sets the Theoretical Boundary
of Muscle Performance?
So, what sets the boundary of muscle performance
for these different types of muscle fibers? This is a
very difficult question to answer because of the
large number of variables associated with physical
activity (e.g., intensity, duration, frequency, acceleration, deceleration, etc.). However, simply
stated the boundary for muscle performance can
be described by the force-velocity relationship.
As shown in Fig. 2, the force-velocity relationship
describes the maximal force that a muscle/muscle
fiber can produce during a single maximal contraction at any given contractile velocity (whether
it be in the lengthening or shortening domain).
Ipso facto this relationship also dictates the
mechanical power and work a muscle/muscle
fiber can produce. When a muscle/muscle fiber
shortens at a slow velocity, then force production
will be very high, and mechanical power will be
low (see Region A in Fig. 2). On the other hand, if
a muscle/muscle fiber shortens at a high velocity,
then force production will be low, as will be
Fig. 2 The boundary of muscle performance is set by the
force-velocity relationship across the spectrum of shortening and lengthening contractions. When muscles have to
work against large loads, the shortening velocity is slow
(see Region A). In contrast, when muscles work against
light loads, then the shortening velocity will be much faster,
V. J. Caiozzo and K. M. Baldwin
mechanical power (see Region B in Fig. 2). As
illustrated in Fig. 2, there is an optimal forcevelocity interaction that results in maximal
mechanical power, which typically occurs at
about 0.3 P0. The shape of the force-velocity
relationship is determined by a complex interaction between (i) the number of myofibrils/sarcomeres in parallel and (ii) the MHC isoform
composition. If a muscle/muscle fiber is required
to perform several repetitive contractions, then it
will be able to work at or near the boundary
established by the force-velocity relationship.
However, as the duration of activity increases,
the muscle/muscle fiber will be forced to work
progressively further below this boundary, as
represented by Region C in Fig. 2.
What Are the Primary Design
Constraints of Muscle Performance?
During a single maximal contraction, the intrinsic
design constraints that limit the performance of
an individual muscle fiber are sarcomeric factors i,
as represented by Region B. Importantly, the force-velocity
relationship also dictates the power and mechanical work a
muscle can produce. As the duration of activity increases,
then muscles are obligated to work progressively further
from the boundary of muscle performance as defined by the
force-velocity relationship (represented by Region C)
Muscle Evolution and Fiber Types
iii, v, and vi, as shown in Fig. 3. If a muscle/muscle
fiber is required to perform oscillatory work,
whereby it undergoes repetitive contractionrelaxation cycles, then the properties of the SR
and Ca++ shuttling between troponin C and the SR
Ca++ ATPase pump (SERCAs) also become
important (see factors ii and iv in Fig. 3). Finally,
if a muscle is required to perform beyond 20–30 s,
then the role of the mitochondria becomes progressively more important with respect to
supporting the metabolic demands of the contractile machinery and the SR.
In thinking about design constraints, it is useful
to think in both quantitative and qualitative terms
(see Fig. 4a). From a qualitative perspective, the
relative volume of a given cellular component is
often expressed as volume density (i.e., volume of
cellular component divided by the total cell volume). In human skeletal, the volume densities of
myofibrils/sarcomeres, SR, and mitochondria are
approximately 80–85%, 5%, and 5%, respectively.
As noted by us previously (Caiozzo 2012), human
muscles with their large volume density of myofibrils (80–85%) and relatively small volume densities of SR and mitochondria (both approximately
5%) evolved in such a manner to maximize force
Fig. 3 Key properties determining the force, velocity,
work, and power that can be produced during single maximal contractions and during oscillatory work (cyclic
5
production at the cost of producing high cycling
rates and higher aerobic capacity. From a qualitative perspective, muscle unloading as occurs in
microgravity produces qualitative shifts (slow to
fast) in the types of molecular motors (i.e., MHC
isoforms) and SERCAs (see Fig. 4b). From a
quantitative perspective, however, it is well
known that muscle unloading reduces the number
of sarcomeres/myofibrils in parallel, resulting in a
significant truncation of the force-velocity relationship, as shown in Fig. 4d. Interestingly, this
truncation can be partially offset by MHC isoform
shifts from slow to fast (Caiozzo et al. 1994, 1996).
The Impact of Microgravity on Design
Constraints
Animal Models to Induce Skeletal
Muscle Atrophy and Functional Deficits
Over the years scientists have established several
models to induce skeletal muscle atrophy/wasting
and functional deficits in nonhuman animals. For
example, three unique models of skeletal muscle
unloading have been established for rats and mice.
phases of contraction-relaxation). Each of the factors listed
represents intrinsic factors with the exception of extracellular matrix collagen
6
Fig. 4 (continued)
V. J. Caiozzo and K. M. Baldwin
Muscle Evolution and Fiber Types
Fig. 4 This figure illustrates the importance of both qualitative (zero-sum game; (a), modifiers of the zero-sum game
(contractile and SERCA isoforms; (b), and quantitative
changes as reflected by losses in the number of myofibrils
and SMART units in parallel (c). As noted in the text, the
primary physiological properties of skeletal muscle are defined
by the properties of the sarcomere, mitochondria, and SR. The
zero-sum game is a qualitative concept that describes the
relative ratios of these three design criteria and can best be
described by volume densities. The volume density of one
design criteria can be expanded but at the cost of one or both
remaining compartments, hence the term “zero-sum game.”
The normal human state is shown in the middle panel, and the
7
panels to the left and right illustrate expansion of the SR and
mitochondrial compartments at the expense of the myofibrillar
volume density, respectively. Within the concept of the zerosum game, muscle physiology can be modified via the presence of contractile and SERCA isoforms, as has been shown to
occur with muscle unloading (see b). From a quantitative
perspective, it is known that muscle atrophy leads to a loss of
myofibrils in parallel, but perhaps even more meaningful, it
leads to a loss of SMART units in parallel, which equates to a
proportional loss of sarcomeres, mitochondria, and SR (see c).
(d) provides a hypothetical illustration of changes in the forcevelocity relationship that are known to occur as a result of the
type of muscle unloading produced in microgravity
8
V. J. Caiozzo and K. M. Baldwin
activity, the effects noted above were reversed
back to a normal state in the soleus muscle
suggesting that the apparent role in the maintenance of posture and low-intensity locomotor
activity plays a critical role in maintaining the
slow contractile phenotype (Thomason et al.
1987).
Nine years later, Caiozzo et al. (1996) were one
of the first to study microgravity-induced transformations of both myosin heavy chain (MHC)
isoforms and contractile properties of both slow
(soleus) and fast (plantaris) skeletal muscles spanning 14 days of spaceflight on the space shuttle.
The key findings were most insightful in that the
force-velocity relationships of the flight soleus
muscles had a significant reduction in maximal
isometric tension ( 37%) and a corresponding
increase in maximal shortening velocity (+20%).
Also, the force-frequency relationship of the flight
soleus muscle was shifted to the right of the
ground-based control soleus muscles. Microgravity had the greatest effect on muscle fiber composition in the slow soleus muscle, with a reduction
in slow muscle fibers and a corresponding
increase in fast muscle fibers categorized as
hybrid fibers. The estimated absolute MHC isoform content was altered to the greatest extent in
the soleus muscles, with significant decreases and
elevation in the slow type I and fast type IIX MHC
isoforms, respectively. Consistent with the protein
data, the flight-type soleus exhibited elevation of
These involve (1) hind limb suspension in which
the hind limbs cannot generate weight-bearing
activities; (2) spinal isolation, which involves a
complete transaction of the spinal cord at both the
mid-thoracic and sacral segments along with complete deafferentation between the two sites to
eliminate
neuromuscular
activity
while
maintaining intact neuromuscular connectivity;
and (3) spaceflight, which involves unloading of
both the whole animal and especially the musculoskeletal system. In all of these models, there are
similar outcomes as delineated below.
In 1987, Don Thomason and associates (1987)
performed a 55-day time-course hind limb suspension study and compared the effects on both
the slow-type soleus muscle (which expresses the
slow type I myosin heavy chain) and the fast-type
plantaris muscle (which expresses primarily the
fast type IIa/IIx myosin heavy chain). Interestingly, the soleus muscle atrophied by approximately 55%, whereas the plantaris muscle
atrophied by only 25% (Fig. 5). This differential
effect was due to the fact that the soleus muscle
lost approximately 80% of the myofibril fraction,
whereas the medial gastrocnemius myofibril fraction approximated only a 30% reduction. Furthermore, it was apparent that there was a de novo
expression of the faster types of myosin in the
soleus muscle. Interestingly, in a group of animals
that were first unloaded for 55 days and then
allowed to recover with normal weight-bearing
Ground Control
0
% Change in Muscle W eight
(r elative to GC)
Fig. 5 Illustration of the
effects of muscle unloading
on slow (soleus) and fast
(medial gastrocnemius;
MG) muscle
¯21%
¯26%
-20
MG
-40
¯35%
Soleus
¯45%
-60
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16
Days of HS Unloading
Muscle Evolution and Fiber Types
the type IIX MHC mRNA isoform. In contrast,
however, the flight fast plantaris muscles had significant increases in the fast type IIB MHC and
mRNA isoform content. The results of this study
suggest that spaceflight of even shorter duration
produces important alterations in the contractile
properties of antigravity skeletal muscle. These
changes are mediated by alterations in MHC phenotype and reductions in skeletal muscle mass and
impact factors iii and v. The findings of this study
are in synchrony with the findings presented
above using the hind limb suspension model in
the Thomason manuscript (Thomason et al.
1987). Further, this study paved the way of demonstrating that the effects of microgravity must be
better understood at the transcriptional, translational, and posttranslational levels.
Of the six factors determining muscle performance (see Fig. 3), the release and sequestration
of Ca++ by the SR is represented by factors ii and
iv. More specifically, the release of Ca++ (step ii) is
dependent on a complex interplay between L-type
voltage-gated Ca++ channels (also referred to as
dihydropyridine receptors because they selectively bind this class of drugs; DHPRs) found in
the membrane of the T-tubules and calcium
release channels (also known as ryanodine receptors because they selectively bind this class of
plant alkaloids) found in the membrane of the
terminal cisternae of the SR. The DHPRs are
arranged in tetrads and interact with every other
RyR. The tetrad/RyR ratio may vary according to
fiber type with the lowest ratio (1:4) occurring in
fast muscles like the extensor digitorum longus
and the highest ratio (1:12 or higher) found in
slow muscle fibers like those found in the soleus
muscle. Currently, it is believed that the opening
of the DHPRs triggers a conformational change in
the RyRs, causing them to open and release Ca++
from the SR into the sarcoplasm where it binds
troponin C (TnC).
The speed of relaxation is dependent on the
Ca++ ATPase pump of the SR (SERCA), which
is responsible for the sequestration of Ca++ (step
iv). There are different isoforms of SERCAs, with
the fast and slow isoforms referred to as SERCA1
(SERCA1a and 1b) and SERCA2 (SERCA 2a and
2b), respectively. SERCAs 1a and 2a are the
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predominant isoforms found in human skeletal
muscle.
One of the first studies to examine the effects of
muscle disuse on SR function was that published
by Kim et al. (1982). These investigators used a
6-week cast immobilization model and studied the
soleus and vastus lateralis (both deep and superficial regions) muscles. One of the unique aspects
of this study is that they studied the Ca++ ATPase
activity of isolated SR fragments and found no
change. Stevens and Mounier (1992) subsequently studied the Ca++ uptake and release of
the SR from muscle fibers taken from the soleus
muscles exposed to 15 days of hind limb suspension. These investigators noted that unloading
produced an increase in Ca++ uptake of skinned
single fibers taken from the soleus muscle such
that they became fast-like. The underlying mechanisms responsible for the increased Ca++ uptake
remain unknown; however, Salanova et al. (2009)
observed that 60 days of head-down tilt bed rest
produced a significant increase in the relative
number of muscle fibers expressing the faster
SERCA1a isoform.
In addition to the above, there has been a keen
interest in the role of weight-bearing and neuromuscular activity in regulating the structural,
functional, biochemical, and molecular properties
of skeletal muscle (Thomason and Booth 1990;
Roy et al. 1996; Baldwin and Haddad 2001). In
2003, Haddad et al. (2003a, b) performed a series
of experiments using the model of spinal cord
isolation (SI) which blocks nearly all the neuromuscular activity while leaving the motor neuronmuscle fiber connection intact in order to dissect
the cellular processes linked to muscle atrophy.
Rats randomly assigned to normal control and SI
groups were studied at 0, 2, 4, 8, and 15 days after
SI surgery. The slow soleus muscle atrophied by
~50%, with the greatest degree of loss occurring
during the first 8 days of SI. This alteration was
similar to the report above in the hind limb suspension study of Thomason et al. (Thomason and
Booth 1990). Interestingly, throughout the SI
duration, muscle total protein concentration was
maintained at the control level, whereas the
myofiber protein concentration steadily decreased
between 4 and 15 days of SI, and this event was
10
associated with a 50% decrease in MHC normalized to total protein concentration. Actin content
relative to the total protein was maintained near
the control value, e.g., the loss of actin protein was
significantly less than the loss of MHC protein.
In addition to the above alterations, marked
reductions occurred in total RNA and DNA content and in total MHC and actin mRNA normalized to 18S ribosomal RNA. These particular
findings suggest that the two key factors modulating muscle atrophy in the SI model are (i) a reduction in ribosomal RNA that is consistent with the
reduction in protein translation capacity and
(ii) insufficient mRNA substrate for translating
key sarcomeric proteins comprising the myofibril
fraction, such as MHC and actin (e.g., the two
proteins that account for the bulk of the contractile
machinery). In addition, the marked selective
depletion of MHC protein in the muscle of the
SI rats suggests that this protein is more vulnerable to inactivity than actin. Collectively, the data
are consistent with the involvement of pretranslational and translational processes in muscle
atrophy across the different models.
Human Models to Induce Skeletal
Muscle Atrophy and Functional Deficits
Similar models, to those of nonhuman models,
have also evolved for producing muscle atrophy
in human subjects. Three models are relevant and
include (i) bed rest in which the subjects are
exposed to head-down tilt spanning for as long
as 120 days; (ii) unilateral lower limb suspension (ULLS) whereby crutches are used to unload
one leg, while the other leg is responsible for
weight bearing; and (iii) spaceflight of varying
duration on either space shuttle or more recently
the International Space Station (ISS). It is interesting to point out that all astronauts perform
some form of physical activity to maintain health
status, thereby providing some degree of muscle
loading.
Bed Rest. As such, a broad database has
evolved to complement what has been learned
from the animal studies. For example, bed rest
studies lasting up to 42 days show that knee
V. J. Caiozzo and K. M. Baldwin
extension (KE) performance is decreased by
~25%. Leblanc et al. (1992) found that peak
torque decreased by 30% and 18% for the KE
and plantar flexors, respectively. In terms of
assessing changes in muscle mass, the most common methods have been magnetic resonance
imaging and ultrasound. A number of bed rest
studies have reported values for the decrease in
the thigh or knee extension muscles ranging from
~6% to 11% after 20 days (Kawakami et al. 2000),
whereas Leblanc et al. (1992) found that
~120 days of bed rest resulted in a 15% decrease
in thigh muscle volume suggesting that much of
the size decrements may occur at relatively early
time points. On the other hand, the cross-sectional
areas of slow fibers from the soleus muscles of
male subjects have been reported to decrease anywhere from 7% to 29% after 60 days of bed rest
and from 35% to 48% after 120-day period
(Shenkman et al. 1998). The fast twitch fibers
from the soleus was reported to decrease by 34%
at 60 days, but no further at 120 days of bed rest
(Shenkman et al. 1998).
Therefore, bed rest effectively imposes
unweighting on the postural antigravity skeletal
muscles, along with a significant decrease in
activity and energy expenditure. This model
allows investigators to study relatively complete
muscle unloading, as well as potential palliative
interventions such as programmed exercise. The
bed rest model is particularly appropriate for integrative,
multi-investigator
investigations
designed to study multisystem effects of reduced
activity and unweighting. This is particularly true
when the bed rest conditions include head-down
tilt for the study of cardiovascular adaptation. In
light of the results available to date, it appears that
bed rest mimics both the magnitude and possible
mechanisms of muscle adaptation seen with
spaceflight.
ULLS. This modality is another ground-based
model for muscle unweighting/unloading. It is an
offshoot of immobilization of the leg that does not
involve constant fixation of the knee joint. This
model historically has involved two approaches:
(i) an older version that involves the use of a
support strap to suspend one lower limb (Berg
et al. 1991; Berg and Tesch 1996) and thus
Muscle Evolution and Fiber Types
prevents weight bearing and (ii) another version
that employs a high-platform shoe on the contralateral limb to prevent weight bearing in the ipsilateral leg (e.g., Ferretti et al. 2001). In each case,
ambulatory activity is performed by using
crutches.
ULLS studies of short duration of 10–21 days
found that knee extension of maximal voluntary
contractions (MVC) decreased by ~12 to 17%
(Berg and Tesch 1996). Longer studies ranging
from 28 to 42 days report that the MVC of the KE
decreased by 20–25% (Dudley et al. 1992). These
observed changes in strength after ULLS appear
to parallel those studies from both bed rest and
spaceflight (see below). The majority of ULLS
studies conducted to date have included MRI
and CT-based measurements of muscle size.
ULLS of 21–28 days duration resulted in ~7%
muscle loss in the thigh and leg (Berg et al.
1991), whereas, after a 35-day protocol, it is
reported to induce a 15% decrease in CSA of the
KE muscles (Ploutz-Snyder et al. 1995; PloutzSnyder et al. 1996). Interestingly, after 42 days of
ULLS, Hather et al. (1992) found that antigravity
muscles of the leg demonstrated the greatest sensitivity to ULLS with 17% and 25% declines in
the CSA of the soleus and gastrocnemius,
respectively.
Compared with bed rest, the development of
the ULLS model is relatively recent. As a result,
fewer studies have included measurements of
muscle fiber size after ULLS. Widrick et al.
(2002) reported that 12 days of unweighting via
ULLS induced a 7% decrease diameter of soleus
fibers, whereas the diameter of the fibers from the
gastrocnemius was not altered. However, Ferretti
et al. (2001) reported that after 42 days of ULLS,
the CSA of muscle fibers from the vastus lateralis
decreased by 12% and 15% for type I and type II
fibers, respectively.
Haddad et al. (2005) evaluated pretranslational markers of protein expression in
human skeletal muscle in response to 5 weeks of
ULLS, including subjects that performed ULLS
and resistance exercise (RE). The goal of this
study was unique in that the study determined
whether alterations in contractile protein gene
expression, e.g., myosin heavy chain and actin,
11
as studied at the pretranslational level, provide
useful molecular markers concerning the deficits
that occur in muscle mass/volume during ULLS,
as well as its maintenance. Muscle biopsies were
obtained from the vastus lateralis of 31 middleaged men and women before and after 5-week
ULLS and ULLS plus in response to ULLS plus
RE. The findings from this study show that there
were net deficits in total RNA, total mRNA, and
actin and myosin heavy chain mRNA levels after
ULLS. However, these alterations were blunted in
the ULLS plus RE subjects (Haddad et al. 2005).
Additional observations involving insulin
growth factor 1 (IGF-1) and its associated receptors and binding proteins suggest that the RE
postures the skeletal muscle for signaling processes that favor a greater anabolic state relative
to that observed in the ULLS group. Collectively,
these findings suggest that molecular markers of
contractile protein gene expression serve as useful
subcellular indicators for ascertaining alterations
in muscle mass in human subjects in response to
altered loading states.
Spaceflight. Both NASA and the Russian space
programs have had space laboratories dedicated to
scientific investigations of the microgravity environment from which several studies have been
published as presented below. Additionally, the
space shuttle provided a platform for performing
experiments designed to assess the effects of
short-term spaceflights concerning skeletal muscle homeostasis. Longer-term muscle physiology
experiments including muscle performance, muscle size, and single muscle fiber analysis have
been conducted more recently. As noted after the
US Skylab series of missions spanning, 28, 56,
and 84 days of exposure to microgravity generally
resulted in decrements in skeletal muscle performance and size (Thornton and Rummel 1977).
Specifically, the strength of knee flexors measured
5 days after landing was decreased by ~20% after
the 28- and 56-day missions but was unchanged
after the 84-day mission (Greenleaf et al. 1989).
Additionally, the results from 140- and 175-day
missions on space station Mir indicated that there
were considerable decrements in gastrocnemius
muscle strength, especially when working with
the isometric and high rate regimens
12
(Kozlovskaya et al. 1981). Another series
(6-month Mir missions) found that isometric maximal voluntary contractions (MVC) of the triceps
surae muscle group decreased by ~42%, where
peak tetanic force (Po) decreased ~25% (Koryak
2001). The results from19 STS crew member who
were in space for ~11 days indicated that maxima
knee extension strength decreased by ~10%,
whereas trunk flexion strength was decreased by
20% (Greenisen and Edgerton 1994). In contrast
to these reports, four crew members from the
17-day STS-78 mission (Life and Microgravity
Sciences Mission) demonstrated no decrease in
calf muscle strength (Narici et al. 1997; McCall
et al. 1999). These latter observations should be
interpreted in the context that NASA flight rules
require that all crew members must exercise on
spaceflight missions of durations longer than
10 days.
The maximal force (Po) that a muscle fiber can
generate is dependent to a large extent on the
number of sarcomeres functioning in parallel
(i.e., the muscle cross-sectional area (CSA)). In
this context, several studies examined the effects
of microgravity on muscle CSA as determined by
various volume and imaging techniques. Results
from the Skylab missions included substantial
decrements in leg volume of 7–10% (Thornton
and Rummel 1977). In contrast, after 140- and
175-day Mir missions, Kozlovskaya et al. (1981)
found only small transient decreases in leg circumference and, therefore, concluded that there
was no great muscular loss in space. However,
after 112–196 days on Mir, Leblanc et al. (2000)
found that crew members had significant
decreases in leg muscle volume (e.g., 19% loss
in gastrocnemius and soleus and 10% loss in the
quadriceps). The results reported by Leblanc et al.
were obtained by using MRI, suggesting that
methodological differences could account for
these diverse findings. It should be pointed out
that flight crews on various missions have participated in widely varying types and amounts of
physical activity, including exercise intended as
countermeasures to muscle loss and general
deconditioning.
Several studies have examined muscle fiber
characteristics after spaceflight. In considering
V. J. Caiozzo and K. M. Baldwin
these results, it must be emphasized that, as with
both strength and whole muscle size measurements, determining of muscle fiber size has been
made by using a number of different methodologies including histochemical sections and single
fiber analysis. Edgerton et al. (1995) found the
size of all muscle fiber types from the vastus
lateralis (VL) decreased after 5–11 days of spaceflight (i.e., type I ~ 16%; IIa, 23%; and IIb
36%). These authors also found that the percentage of type I fibers decreased (6–8%). On the
other hand, after the 17-day LMS Space Lab Mission, Trappe et al. (2001) found that there was no
change in the size of single muscle fibers from the
soleus and gastroc muscles of four astronaut crew
members. However, there was a great deal of
between-subject variability in this mission. As
noted by the investigators, it is not clear whether
these intersubject differences in muscle fiber
response were attributed to spaceflight or were a
function of the countermeasure exercise
performed by the individual crew members.
Thus the science field has a great challenge to
learn more details about what impacts human
skeletal muscle during long-duration spaceflights
since it is now routine for astronauts to live in
space for 6 months and even 1-year intervals.
Some of these details are considered in the following entry, whereby we address key pathways
associated with protein synthesis, protein degradation, global models of muscle atrophy, and
potential countermeasures.
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