INTRODUCTION
CHAPTER 1
General introduction
9
CHAPTER 1
Fibre type composition of limb muscles
Any voluntary activity of skeletal muscle
is under control of the central nervous system, which executes such control via the
so-called “final common path”—
motoneurones localized in the brainstem
or spinal ventral cord (Sherrington, 1906).
Each single motoneurone innervates a homogeneous population of muscle fibres,
together composing a functional entity—
the motor unit. Within a motor unit, the
properties of the innervating motoneurone
are generally well matched to those of its
innervated muscle fibres (Burke, 1981;
Kernell 1992). However, there are different types of motor units containing different types of muscle fibres. Thus, mammalian skeletal muscle is not a uniform
tissue.
Traditionally, muscles were anatomically classified into red (slow) and white
(fast) based on their colour, the colour difference emerging due to differences in the
content of myoglobin, cytochrome oxidase and capillaries. With the arrival of
modern histochemistry it became evident
that such differences also existed between
individual muscle fibres, contained within
single muscles. The various fibre and
motor unit types can be classified on the
basis of differences in morphological, biochemical, histochemical, and physiological properties, which has led to a variety
of nomenclatures (e.g. Brooke and Kaiser, 1970; Burke et al, 1971; Edgerton and
Simpson, 1969; Peter et al, 1972; Stein
and Padykula, 1962; reviews: Burke,
1981; Pette and Staron, 1990, 1997). The
most commonly used physiological categorization separates motor units into
types S (slow-twitch fatigue resistant), FR
(fast-twitch fatigue resistant) and FF (fast10
twitch fatiguable) (Burke, 1981; Burke et
al., 1971; 1973). Histochemically, muscle
fibres are often subdivided into types I,
IIA and IIB, as based on the pH sensitivity of their myofibrillar ATPase
(mATPase) (Brooke and Kaiser, 1970;
Guth and Samaha, 1970). Direct comparisons between histochemical and physiological properties have demonstrated
that type I fibres tend to be slow and type
II fibres fast. Combinations of staining for
mATPase and metabolic enzymes are
typically used for a third classification
into SO (slow-oxidative), FOG (fast-oxidative-glycolytical), and FG (fastglycolytical) muscle fibres (e.g. Peter et
al., 1972). The various classification systems correspond such that type S ~ I ~
SO, type FR ~ IIA ~ FOG and type FF ~
IIB ~ FG.
It should be noted that any classification system of muscle fibre types is
more or less arbitrary because most properties of muscle fibres show a continuous
gradation. Even within single muscles,
properties vary between fibres belonging
to the same category or “type”, and the
same “type” of fibre may have quite different properties in different animal species. One of the least gradual and most
distinct classifications is that between type
I and II fibres, as seen in mATPase histochemistry. This is the classification used
in the present investigation.
As compared to the type II fibres, the
type I fibres have slow isometric twitches,
a slow shortening speed, a predominantly
oxidative metabolism and a great resistance to fatigue. They occur in most mammalian muscles but tend to be particularly
prominent in muscles with pronounced
postural functions. They are well adapted
to such functions thanks to their low rate
INTRODUCTION
of ATP usage in near-isometric (postural)
contractions. On the other hand, the type
II fibres have a high speed of shortening
and are well equipped for the rapid
anaerobic mobilization of energy (well
provided with glycolytic enzymes): these
fibres are adapted for rapid and/or powerful contractions used in movements.
The mATPase is part of the myosin
molecule, whose properties are important
for determining the maximal shortening
speed of a muscle fibre. When compared
under “life-like” biochemical conditions,
myosins with a high mATPase activity
tend to be more rapidly contracting than
those with a lower one (Barany et al.,
1965; Seidel et al., 1964). It should be
noted, however, that the common kind of
histochemical mATPase staining is based
on differences in pH sensitivity between
the various myosin isozymes and not on
differences in their normally expressed
enzyme activity.
The myosin molecule consists of two
heavy and four light chains. Different fibre types (e.g., types I and II) contain different specific sets of the myosin heavy
and light chains (cf. Billeter et al., 1981;
Salviati et al., 1982; Young, 1982). Besides the adult types of myosin, there are
also isoforms which appear only during
the course of early stages of development
(embryonic and neonatal heavy chains; cf.
Hoh and Yeoh, 1979; Whalen et al., 1981).
Differences in myosin composition covary with numerous other aspects of biochemical specialization, such as differences in thin filament composition (e.g.
regulatory proteins; cf. Dhoot and Perry,
1979; Mikawa et al., 1981), sarcoplasmic
reticulum and metabolic enzyme equipment (see above).
Differentiation of muscle fibre types
How do muscle fibres differentiate into
different types? It seems clear that the first
stages of muscle fibre differentiation take
place already in early prenatal periods.
Mammalian skeletal muscles are progressively built up from successive generations of cells (cf. Ashmore et al., 1972;
Kelly and Zacks, 1969). At the inception
of myogenesis, myoblasts in the primary
muscle mass replicate and fuse to form
the primary generation of myotubes,
which will largely differentiate into the
adult type I (slow) fibres (Rubinstein and
Kelly, 1981). Later on, a secondary generation of myotubes forms, typically
growing along the sides of the primary
myotubes and emerging through fusion of
newly replicated myoblasts (Ontell,
1977). The second generation of
myotubes will predominantly develop
into adult type II (fast) fibres (Rubinstein
and Kelly, 1981). Following these initial,
genetically pre-programmed stages of
muscle development, the expression of
muscle fibre properties (including its
myosin composition) may be markedly
influenced and altered by several different factors, including hormone levels (particularly thyroid), the kind of innervation
(“fast” or “slow” motoneurones), and the
kind and extent of muscle use. The primary myotubes have been demonstrated
to develop even without innervation. Development of the second generation does,
however, commonly require innervation
and perhaps even activity (Harris, 1981;
cf., however, Condon et al., 1990).
The homogeneity of muscle fibres
within the same motor unit (cf. Gauthier
et al., 1983; Kugelberg and Lindegren,
1979) is partly a consequence of cell-rec11
CHAPTER 1
ognition mechanisms operating between
different types of motoneurones and
muscle fibres during early development
(review: Jansen and Fladby, 1990). The
unit homogeneity is further promoted by
the fact that the muscle fibre properties
are influenced by motoneuronal activation patterns: a given motoneurone will
have a similar influence on all its muscle
fibres. It is evident that various training
programme can alter muscle fibre type
composition via alterations of myosin
isoform expression (cf. Adams et al.,
1993; Andersen et al., 1994; Fitzsimons
et al., 1990; Roy et al., 1997). Changes in
muscle use may also be the (partial) cause
of alterations in muscle composition during postnatal growth (e.g. as animals get
heavier and develop other movement patterns; cf.Goldspink and Ward, 1979;
Kugelberg, 1976). The alteration of
muscle fibre type composition induced by
various training programmes may also be
taken as a consequence of changes in
muscle usage. Finally, in old age,
motoneurones start to die off and this is
likely to be one of the main reasons for
the changes taking place in muscle fibre
composition during ageing.
There have been many reports concerning the influence of hormone levels
on fibre type transformation and/or myosin isoform expression. Izumo et al (1986)
found that the MHC multigene family responded to thyroid hormone in a highly
tissue-specific manner. More recently,
Larsson et al (1995) confirmed that a hyperthyroid state induced a dramatic slow
to fast transformation in slow twitch
muscle (soleus) but little or none in fast
twitch muscle (extensor digitorum longus). However, there is still some disagreement about the effect of thyroid hor12
mone (T3) on muscle fibre type transformation (cf. Suwa et al., 1998). Some other
hormones, such as growth hormone, are
also considered to be involved in the processes of muscle fibre-type transformation or myosin expression (Ayling et al.,
1989; Loughna and Bates, 1994).
In summary, muscle fibres do not
rigidly maintain their original preprogrammed characteristics, but their
properties can be adjusted to changing
needs throughout life.
Spatial distribution of different muscle
fibre type: fibre type regionalization
As seen in a histochemically stained
cross-section, a typical chess-board
“mosaic” of different fibre types is often
shown within a given muscle region (e.g.,
types I and II). Thus, muscle fibres of a
given type have a distinct tendency to be
surrounded by fibres of a different type.
This arrangement has been statistically
confirmed to be non-random (Venema,
1988), and it might facilitate a reciprocal
exchange of metabolites like lactate
between the fibre types (Grotmol et al.,
1988; also cf. Essen et al., 1975). On a
larger scale, uneven distributions of
muscle fibre types across whole crosssections have been frequently noted (fibre
type “regionalization”; reviews:
Armstrong, 1980; Kernell, 1998).
It has since long been realized that,
in experimental animals, whole slow
“red” muscles often tended to lie deeper
than their many fast “white” synergists.
At the beginning of the 1950’s, an
analogous depth-related distribution
pattern of muscle fibre types was reported
to exist also within a single “fast” muscle
(cat tibialis anterior, “depth” in terms of
INTRODUCTION
perpendicular distance to body surface;
Gordon and Philips, 1953). In the 1960’s,
it became apparent that such patterns of
organization existed within many large
single muscles, such as the triceps surae.
However, the phenomenon has not yet
been thoroughly studied as to establish
whether there is a generalized pattern of
fibre type regionalization in vertebrate
muscles. For instance, in many of the
human muscles studied by Johnson et al.
(1973) no significant difference seemed
to exist between the fibre type
composition of “deep” vs. “superficial”
sites (see re-analysis in Kernell, 1998).
Furthermore, in fish, the “red” type I
fibres tend to be predominantly superficial
(e.g. Rome et al., 1988) and in the turtle
various patterns of regionalization were
reported for different hindlimb muscles,
including an accumulation of type I fibres
at the muscle centre (iliofibularis, Laidlaw
et al., 1995).
The relative lack of detailed
knowledge concerning the general
patterns of fibre type regionalization has
partly to do with a lack of suitable
quantitative methods. Previous measurements of fibre type regionalization have
often been based on assessments of fibre
type composition within only a few
“characteristic” sampling areas (e.g.
“deep” vs. “superficial”). In the context
of a continuously varying fibre type
composition within a muscle crosssection, such methods give only a coarse
estimate of the direction and degree of
regionalization. In some cases, more
graded and continuous measurements of
fibre type distribution have been tried. For
example, Pullen (1977a, b) counted the
percentages of different fibre types along
imaginary guidelines in a deep-superficial
and/or medial-lateral direction. Even this
more detailed description does not,
however, provide general figures for the
degree and/or direction of fibre type
regionalization which can be efficiently
used for comparisons between different
(or differently treated) muscles.
An increased knowledge concerning
patterns of fibre type regionalization is
important for theoretical as well as
practical reasons. The common existence
of fibre type regionalization suggests that
this organization may provide an animal
with a functional advantage of some kind.
Furthermore, the phenomenon demonstrates that some of the mechanisms
underlying fibre type differentiation are
clearly topographically organized. As a
first step toward elucidating both these
points, more has to be known about how
fibre type regionalization actually
manifests itself in adult animals. Does it
appear in all muscles of a limb or only in
the large and dominating ones? Are there
similar aspects of topographical
organization between differently located
muscles (or between muscles of different
functional properties)? From a practical
point of view, an increased knowledge
about the patterns of fibre type
regionalization is important as a
background for the interpretation of
pointwise samples of muscle composition
(biopsies) or activity (electromyography);
both kinds of techniques will give
markedly different results depending on
whether the sample was taken from
muscle portions rich or poor in the “slow”
type I fibres.
Questions concerning the normal
patterns of fibre type regionalization are
not limited to fibre type distributions
within cross-sections but include also the
13
CHAPTER 1
lengthwise dimensions. In mammals,
most muscles probably show a pinnate
architecture (pinnate muscle), and in such
cases the muscle fibres will be shorter than
the muscle as a whole, i.e. different
individual muscle fibres may be seen in
cross-sections taken at different
lengthwise sites along the muscle. This
may also be the case in some parallelfibred muscles in which successive fibres
may be serially linked (cf. Heron and
Richmond, 1993; Loeb et al., 1987).
Although lengthwise differences in fibre
type composition have indeed been noted
for a number of muscles (e.g. Gardiner et
al., 1991; Lexell et al., 1994; Punkt et al.,
1998), this aspect of fibre type
regionalization has been even less well
studied than the organization within crosssections through the muscle “belly”.
Muscle denervation and reinnervation
in adults
Transecting a peripheral axon or nerve
leads to the degeneration of its distal
stump (Wallerian degeneration) and,
consequently, denervation of the
respective muscles. Thereafter, the nerve
fibres can grow out again and make
functional connections with any
denervated muscle fibres that they might
come across. However, in adult life motor
axons have lost their capacity for finding
their correct target muscle (Weiss and
Hoag, 1946; Brushart and Mesulam,
1980; Gillespie et al., 1986; Thomas et
al., 1987; Bodine-Fowler et al., 1997), and
“slow” or “fast” motoneurones are also
largely incapable of recognizing their
target fibres as being “slow” or “fast”. As
motoneurones generally have an effect on
the properties of their innervated muscle
14
fibres (Romanul and van der Meulen,
1966), the more or less random
reinnervation of a mixed muscle will lead
to a respecification of properties of many
of the muscle fibres, resulting in a rematching between muscle fibre and
motoneurone properties (Mendell et al.,
1994). For a given motoneurone, many
of the reinnervated muscle fibres will tend
to lie close together. Therefore, a most
striking sign of muscle denervation and
reinnervation is the appearance of groups
of neighbouring fibres of the same
histochemical type (“fibre type
grouping”; Karpati and Engel, 1968
Kugelberg et al., 1970; Vetter et al.,
1984), a useful sign of neurogenic
problems in the clinical diagnosis of
muscle disease (Dubowitz and Brooke,
1973). The degree to which this
phenomenon is manifested varies
considerably with the circumstances
under which reinnervation takes place (cf.
Rafuse and Gordon, 1996; Unguez et al.,
1996); some muscle fibres even appear
relatively resistant to the potential typechanging influences of the innervating
axon (Unguez et al., 1993; Unguez, et al.,
1995).
With regard to fibre type
regionalization, the effects of muscle
denervation and reinnervation have so far
been relatively little studied. In a few
published reports it was noted that
relatively normal patterns of regionalization seemed to re-appear (fast fibres,
cat gastrocnemius lateralis, Foehring et
al., 1987; fast fibres, mouse tibialis
anterior, Parry and Wilkinson, 1990; slow
fibres, cat gastrocnemius medialis, Rafuse
and Gordon, 1996). These interesting
observations were, however, of limited
extent and open for alternative
INTRODUCTION
interpretations. Few muscle species were
studied, measurements were limited to
single-level cross-sections, and
lengthwise aspects of fibre type regionalization were not investigated.
Furthermore, the authors themselves felt
uncertain whether pre- and postreinnervation patterns of regionalization
might have resembled each other simply
because (most of) the reinnervated muscle
fibres might have failed to change their
type-specific properties. Hence, more
extensive and precise investigations were
clearly needed.
Aims and contents of the thesis
As a background for the further analysis
of the mechanisms and functional consequences of fibre type regionalization, we
have performed a thorough quantitative
description of this phenomenon for
muscles of the lower hindlimb in commonly studied laboratory animals. As a
first step toward the experimental analysis of mechanisms involved, we have also
studied the effects on fibre type
regionalization of denervation and re-innervation.
Essential for the performance of all
the present studies was the development
of suitable quantitative methods and concepts. In Chapter 2, methods are described for: (1) delineating the muscle
region containing the “target” fibres (typically type I fibres), and (2) assessing the
direction and degree of heterogeneous
target fibre accumulation within the
muscle (target fibre “eccentricity”). The
target fibre region was quantified using
two different procedures: (a) the well-established “convex hull” method (Cormen
et al., 1990), and (b) a newly developed
“sector” method. The direction and degree of target fibre eccentricity was quantified using a newly developed procedure
for calculating the direction and length of
a “mass vector”. This vector is a line connecting the centre of the whole muscle
cross-section to that for the sub-population of target fibres.
In Chapter 3 these new procedures are
used for determining the patterns of type
I fibre regionalization for midlevel sections of all the ankle-traversing muscles
of the rat’s lower hindlimb. A distinction
is made between “area” regionalization
(type I fibres restricted to part of the crosssection) and “vector” regionalization
(type I fibres eccentrically distributed
within the cross-section). Comparisons
were made between the intra-muscular
patterns of fibre type regionalization and
the intra-limb position of the respective
muscles.
In Chapter 4 lengthwise aspects of fibre type regionalization are analyzed for
a subset of 5 hindlimb muscles of the rat.
In addition, crucial aspects of muscle architecture were also measured for these 5
muscles; this was needed for interpretation of the measurements of fibre type distribution.
In Chapter 5 comparisons of type I
fibre type regionalization are made between homologous muscles of mouse, rat
and rabbit. One of the motivations for
doing this was to try to establish which
aspects of the fibre type regionalization
are species-specific and, hence, possibly
related to functional requirements.
In Chapter 6 it is studied whether normal patterns of type I fibre regionalization
would become re-established following
muscle denervation and re-innervation.
During development, the axons of “fast”
15
CHAPTER 1
and “slow” motoneurones are apparently
guided toward different muscle regions as
the characteristic patterns of fibre type
regionalization are being produced. One
of the motivations for the experiments of
Chapter 6 was to try to find out whether
such regional axon guidance mechanisms
would still be operative in the adult animal. This seemed indeed to be the case.
The analysis of these processes was con-
tinued in Chapter 7 in which we tried to
find out more about the axonal guidance
mechanisms by studying how the re-establishment of the type I fibre
regionalization was influenced by the conditions under which reinnervation took
place.
Finally, the main findings of the thesis are summarized in Chapter 8.
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INTRODUCTION
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CHAPTER 1
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