Muscle and Nonmuscle Contractile Systems
O xidative
F? p h o sp h o ry latio n H20
P h o s p h o c re a tin e
C re atin e
P h o s p h o c re a tin e
C re atin e
F IG U R E 2 1 -1 3
M itochondria
C y to so l
M yofibrils, sa rc o p la s m ic
reticulum , etc.
Phosphocreatine shuttle. A myokinase (adenylate kinase) cascade between
oxidative phosphorylation and creatine kinase (CK) has been postulated. A
similar myofibrillary cascade may exist at the myofibrillar ATPase site.
however, CK and glycolytic enzymes are not colocalized.
Phosphocreatine can be replenished rapidly only by ox-
idative metabolism.
In addition to its energy transport function, phospho-
creatine functions as an intracellular energy store. ATP
inhibits mitochondrial respiration, limiting the maximum
achievable concentration of ATP, but phosphocreatine can
accumulate without inhibiting respiration and ATP syn-
thesis. Phosphocreatine provides a reserve of immediately
available energy that can be used for brief bursts of activ-
ity as in throwing or jumping, and which is able to cover
the energy needs for a few seconds at the beginning of
sprint-type activity while glycolysis is accelerating.
Supplementation with creatine has not been found to
enhance aerobic work performance despite measurable in-
creases in muscle creatine and phosphocreatine, suggest-
ing that energy transfer in muscle cells is not normally lim-
ited by the total creatine concentration. However, ability to
perform intermittent high-intensity work is enhanced, in-
dicating that the energy storage function of PC is increased
by creatine supplementation.
Creatine kinase (also called creatine phosphokinase, or
CPK) is a dimer of subunit molecular weight 40,000. The
brain isozyme is a dimer of B subunits. In skeletal mus-
cle, the principal form is a homodimer of M subunits. In
cardiac muscle, 80-85% of the CK is MM, the balance is
MB. These isozymes are electrophoretically distinct, as is
mitochondrial CK. Depending on fiber type, 10-30% of
CK activity is on the outer side of the inner mitochondrial
membrane, 3—4% is at the M-lines, and the remainder is in
the cytoplasm or bound to SR, sarcolemma, or other sites
of ATP utilization.
Measurement of serum concentration of total CK and
CK-2 (i.e., MB) have long been used to assess the extent
of myocardial damage in suspected MI (Chapter
). Mea-
surement of LDH isozymes has been used similarly. In
recent years, however, reliance on cardiac troponin assays
has increased and use of CK and LDH assays will probably
Regulation of Smooth and Cardiac Muscle
In all the actin-based motility systems, and especially
skeletal, cardiac and smooth muscle, contraction is initi-
ated primarily by an increase in cytoplasmic [Ca2+]. How-
ever, the major differences in histology and function of
these muscle types are associated with great variety in how
contraction is controlled. Smooth muscle especially dif-
fers from the model presented for skeletal muscle. Skeletal
muscle is activated by Ca2+ released from SR in response
to sarcolemmal action potentials. Ca2+ exerts its effect by
binding to troponin on the thin filaments, which reverses
the tropomyosin inhibition of cross-bridge formation.
Smooth muscle is much more dependent on entry of ex-
tracellular calcium. Smooth muscle cells are much smaller,
having lengths about equal to the diameter of small skeletal
muscle fibers, and so have much bigger surface-to-volume
ratios than skeletal muscle cells. Therefore, Ca2+ en-
try from the extracellular space can increase cytoplasmic
[Ca2+] much more readily in smooth muscle than in skele-
tal muscle. Most smooth muscle accordingly need not de-
pend on Ca2+ release from SR, may not have much SR, and
does not need action potentials to trigger SR Ca2+ release.
Smooth muscle exhibits very diverse behaviors depend-
ing on which control mechanisms are present. Vascular
smooth muscle, for example, lacks fast voltage-dependent
Na+ or Ca2+ channels and so does not have action po-
tentials or Ca2+ spikes. It has slow voltage-dependent
Ca2+ channels that admit calcium in a graded fashion in
response to fluctuations in membrane potential induced
by humoral or transmitter effects on membrane ion con-
ductances, and it has several membrane receptor-initiated
second-messenger cascades that control Ca2+ entry and
Ca2+ release from its limited SR, and which moderate the
effectiveness of Ca2+. Vascular smooth muscle contrac-
tion is thus tonic rather than phasic, and is very dependent
on extracellular Ca2+; therefore Ca2+ channel blockers ef-
fectively inhibit contraction. In contrast, gut smooth mus-
cle does have fast voltage-dependent channels sufficient
to produce action potentials and more SR than vascular
smooth muscle, and also has gap junctions through which
ion fluxes can occur. It also has receptor-mediated Ca2+
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