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chapter 21
Muscle and Nonmuscle Contractile Systems
such as mexilitine, and by acetazolamide. Several chan-
nelopathies are listed in Table 21-5.
Metabolic disorders of muscle include those of glyco-
gen storage, substrate transport and utilization, and elec-
tron transport chain and ATP metabolism. Some produce
dynamic syndromes with symptoms occurring primarily
during exertion, some cause degenerative syndromes, and
some produce both. A few are discussed below.
Degenerative Syndromes
Acid maltase
is a lysosomal enzyme that is not in the en-
ergy pathway of the cell, so that its deficiency does not
produce dynamic symptoms in muscle. Also called a - 1,4-
glucosidase, acid maltase hydrolyzes the a -1,4 bonds in
glycogen. Since lysosomes degrade glycogen along with
other macromolecules in the normal process of cellular
turnover, this deficiency causes marked accumulation of
glycogen in lysosomes. This leads to a vacuolar degen-
eration of muscle fibers. Heart and other tissues are also
affected. Deficiency of debranching enzyme (amylo-1,6-
glycosidase) is another disorder of glycogen metabolism.
Since phosphorylase cannot act at or near branch points
(Chapter 15), lack of debranching enzyme results in great
accumulation of limit dextrins in muscle, liver, heart,
and leukocytes, with swelling and functional impairment.
Since this enzyme is in the energy pathway, its absence
causes dynamic symptoms and, more importantly, vacuo-
lar degeneration. Carnitine deficiency causes a disorder
of lipid metabolism. Carnitine is derived both from the
diet and from £-N-trimethyllysine produced by catabolism
of methylated proteins including myosin, and is required
for the transport of fatty acids across the mitochondrial
membranes (Chapter 18). If any of the enzymes or cofac-
tors required for carnitine synthesis are deficient or de-
fective, carnitine deficiency may develop. This limits the
energy supply available from /6-oxidation, and causes a
lipid storage myopathy.
Dynamic Syndromes
Myophosphorylase deficiency
is the classic example of
a carbohydrate-related dynamic syndrome. Affected per-
sons are unable to mobilize glycogen; therefore they can-
not perform high-intensity work and must rely extensively
on lipid metabolism. Several other defects of glycolysis
produce similar symptoms. All are characterized by in-
ability to do anaerobic work and to produce lactate during
ischemic exercise, which is the basis for the customary
screening test for these disorders. Patients are asked to
perform maximal hand grip contractions at the rate of one
per second for 60 seconds with the forearm circulation
occluded by inflation of a cuff on the upper arm. Follow-
ing release of the cuff pressure, venous effluent from the
exercised arm is sampled and analyzed for lactate. In ad-
dition to reduced anaerobic work capacity, the low flux
through glycolysis reduces maximal muscle power output
and maximal aerobic power as well. In phosphorylase
deficiency, muscular performance can often be improved
by glucose infusion, while patients with other defects of
glycolysis are dependent on lipid metabolism and show
little or no improvement with glucose infusion.
21.5 Nonmuscle Systems
Actin
Actin is present in all eukaryotic cells where it has struc-
tural and mobility functions. Most movement associated
with microfilaments requires myosin. The myosin-to-actin
ratio is much lower in nonmuscle cells, and myosin bun-
dles are much smaller (10-20 molecules rather than about
500), but the interaction between myosin and actin in non-
muscle cells is generally similar to that in muscle. As in
smooth muscle, myosin aggregation and activation of the
actin-myosin interaction are regulated primarily by light
chain phosphorylation. Myosins involved in transporting
organelles along actin filaments are often activated by
Ca-CaM.
Actin filaments are relatively permanent structures in
muscle, whereas in nonmuscle cells microfilaments may
be transitory, forming and dissociating in response to
changing requirements. The contractile ring that forms
during cell division to separate the daughter cells and the
pseudopodia formed by migrating phagocytes comprise
transient actin filaments. Belt desmosomes in epithelial
cells and microvilli on intestinal epithelial cells comprise
relatively permanent filaments.
The rate-limiting step in actin polymerization appears
to be nucleation, the formation of an actin cluster large
enough (typically three or four G-actins) for the rate of
monomer association to exceed the rate of dissociation.
Once filaments of this size form, they continue to grow,
and the concentration of G-actin monomers decreases un-
til it is in equilibrium with F-actin. The concentration of
monomeric actin at equilibrium is called the critical con-
centration, Cc.
In vitro,
Cc is 0.1 mM. The value
in vivo
is
variable, depending in part on the concentration of ATP.
In the presence of ADP, instead of ATP, both ends of the
filament grow at the characteristic slow rate. ATP speeds
up the rate of polymerization and lowers the effective Cc.
If nascent actin filaments anchored to the cytoskeleton
(by binding proteins such as those listed in Table 21-6)
