98
SECTION II
Physiology of Nerve & Muscle Cells
CLINICAL BOX 5–1
Disease of Muscle
have in common exercise intolerance and the possibility of
muscle breakdown due to accumulation of toxic metabolites.
Muscular Dystrophies
The term
muscular dystrophy
is applied to diseases that cause
progressive weakness of skeletal muscle. About 50 such diseas-
es have been described, some of which include cardiac as well
as skeletal muscle. They range from mild to severe and some are
eventually fatal. They have multiple causes, but mutations in the
genes for the various components of the dystrophin–glycopro-
tein complex are a prominent cause. The dystrophin gene is one
of the largest in the body, and mutations can occur at many dif-
ferent sites in it.
Duchenne muscular dystrophy
is a serious
form of dystrophy in which the dystrophin protein is absent
from muscle. It is X-linked and usually fatal by the age of 30. In a
milder form of the disease,
Becker muscular dystrophy,
dys-
trophin is present but altered or reduced in amount. Limb-girdle
muscular dystrophies of various types are associated with muta-
tions of the genes coding for the sarcoglycans or other compo-
nents of the dystrophin–glycoprotein complex.Ion Channel Myopathies
In the various forms of clinical
myotonia,
muscle relaxation is
prolonged after voluntary contraction. The molecular bases of
myotonias are due to dysfunction of channels that shape the
action potential. Myotonia dystrophy is caused by an autoso-
mal dominant mutation that leads to overexpression of a K
+
channel (although the mutation is
not
at the K
+
channel). A
variety of myotonias are associated with mutations in Na
+
channels (eg, hyperkalemic periodic paralysis, paramyotonia
congenita, or Na
+
channel congenita) or Cl- channels (eg,
dominant or recessive myotonia congenita).
Malignant hyperthermia is another disease related to dys-
functional muscle ion channels. Patients with malignant hy-
perthermia can respond to general anesthetics such as hal-
othane by eliciting rigidity in the muscles and a quick
increase in body temperature. This disease has been traced
to a mutation in RyR, the Ca
2+
release channel in the sarco-
plasmic reticulum. The mutation results in an inefficient
feedback mechanism to shut down Ca
2+
release after stimu-
lation of the RyR, and thus, increased contractility and heat
generation.
Metabolic Myopathies
Mutations in genes that code for enzymes involved in the me-
tabolism of carbohydrates, fats, and proteins to CO
2
and H
2
O
in muscle and the production of ATP can cause
metabolic my-
opathies
(eg, McArdle syndrome). Metabolic myopathies allTABLE 5–1
Steady-state distribution of ions
in the intracellular and extracellular compartments
of mammalian skeletal muscle, and the equilibrium
potentials for these ions.
Ion
aConcentration (mmol/L)
Equilibrium
Potential (mV)Intracellular
FluidExtracellular
Fluid
Na
+
12 145 +65
K
+
155 4 –95
H
+
13
×
10
–5
3.8
×
10
–5
–32
Cl- 3.8 120 –90
HCO
3 –
8 27 –32
A
155 0 ...
Membrane potential = –90 mV
a
A
- represents organic anions. The value for intracellular Cl
- is calculated from the
membrane potential, using the Nernst equation.
- is calculated from the
FIGURE 5–5
The electrical and mechanical responses of a
mammalian skeletal muscle fiber to a single maximal stimulus.
The electrical response (mV potential change) and the mechanical re-
sponse (T, tension in arbitrary units) are plotted on the same abscissa
(time). The mechanical response is relatively long-lived compared to
the electrical response that initiates contraction.0 5 10 15 20 25
ms1000300TmV