The muscle physiology and histochemistry of a hereditary neuromuscular
syndrome of the mouse, “arrested development of righting response”
(ADR), was studied. The speed of single twitches of fast ADR limb muscles
was normal up to an age of about 60 days but decreased at later ages. At
any age between 10 and 120 days postnatal, fast and slow muscles of the
mutant displayed after-contractionsof 1-3 (5) seconds duration. These coincided with electrical after-activity of muscle, as demonstrated by electromyography. After-contractions and EMG signals were suppressed by the
membrane-stabilizing drug tocainide. These physiological data suggest
that ADR is a myotonia. With a few exceptions, limb and trunk muscles of
ADR animals showed a uniform oxidative phenotype with a lack of large
diameter glycolytic fibers. The histochemical muscle phenotype of the ADR
mouse was partially reversed by a long-term treatment with tocainide.
MUSCLE ?i NERVE 11:433-439 1988
THE MYOTONIC MOUSE MUTANT ADR:
PHYSIOLOGICAL AND HISTOCHEMICAL
PROPERTIES OF MUSCLE
JUTTA REININGHAUS, MS, ERNST-MARTIN FUCHTBAUER, PhD,
KORDULA BERTRAM, and HARALD JOCKUSCH, PhD
I n the mouse, a large number of mutations has
been described that affect the differentiation,
maturation, or maintenance of the neuromuscular
system.”,24 Watts et al.28,29have described the
unusual motor behavior and the “greater redness
of muscle” of mice affected by a particular autosoma1 recessive mutation, “arrested development
of righting response” (adr). We could show that
the abnormal motor behavior is due to after-contractions of muscle and that the calcium-binding
protein, parvalbumin (PV), is greatly reduced in
ADR* fast muscle. On the basis of these findings,
the possibility was raised that the reduced PV content in ADR muscle may interfere with an effi-
ve-
cient calcium removal from the cytosol durin
laxation and thereby cause after-contractions.
However, the observation of repetitive action
potentials in ADR sternocostalis muscle’”16 suggested an alternative possibility, that ADR is a
myotonia, i.e., that the abnormal motor behavior
is caused by a muscle membrane abnormality.
In the present work, ADR muscle is further
characterized by enzyme histochemistry, contraction measurements, electromyography, and pharmacological experiments. The results support the
second hypothesis and suggest that the overt biochemical abnormalities of ADR muscle are a secondary consequence of myotonia.
MATERIAL AND METHODS
*Lower case mutant symbols designate alleles, upper case symbols
designate phenotypes.
From the Developmental Biology Unit, University of Bielefeld, Bielefeld,
Federal Republic of Germany.
Acknowledgments: We thank Drs. F.G.I. Jennekens (Utrecht), D. Parry
(Ottawa), R. Rude1 (Ulm), G. VrbovA (London), and W Wallinga de
Jonge (Enschede) for discussions and K. Ewald. R. Klocke, and K. Weigel for help in preparing the manuscript Supported by Deutsche Forschungsgemeinschaft (Project Jo 8417 and SFB 223 “Pathobiology of Cellular Interactions”).
Address reprint requests to Dr. Jockusch at the Developmental Biology
Unit, W7, University of Bielefeld, POB 8640, D-4800 Bieiefeid 1, FRG
Biological Material. Breeders for the mutation
arrested development of righting response on
A2G background had been obtained in 1982 from
Drs. R.L. Watts and D.L. Watts, Guy’s Hospital,
London.
Experimental animals were homozygous mutant mice (designation of the phenotype ADR)
and nonaffected (heterozygous or homozygous
wildtype) sex-matched littermates or sex- and agematched animals of the same colony (designated
“wildtype,” WT).
Accepted for publication March 17, 1987
0148-639W110.510433 $04.0017
0 1988 John Wlley & Sons, Inc.
Myotonic Mouse Muscle
Measurements. Isometric contractions were recorded in situ or from isolated mus-
Contraction
MUSCLE & NERVE
May 1988
433
cles. T h e muscles were warmed and kept moist by
continuous superfusion of a solution containing
137 mM NaCI, 5 mM KCl, 2 mM CaCl,, 1 mM
MgCI,, 1 m V N aH2 P0 4 ,and 24 mM NaHC03.14
Isolated muscles were bathed in the same solution
containing 11 mM glucose and saturated with
95% 0,, 5 % CO,. Except when stated otherwise,
muscles were kept at 34-35°C. For the in situ recordings the animals were anesthetized with nernhutal (0.1 mg/g body weight) and the muscles dissected. T h e knee joint was held in fixed position
by a clamp. l h e distal tendon was tied to the
stainless steel connection of a force transducer
(resonant frequency 500 I Iz), and the muscles
were then stretched to their original length. Muscles were usually stimulated directly with constant
voltage using two platinum electrodes. T h e tension signals were monitored o n a VUKO VKS
22-60 digital storage oscilloscope (VUKO VKS
22- 16, VUKO, Darmstadt, FRG) connected to an
Apple IIe computer (Apple Computer Inc., Cupertino, CA). T h e graphs show redrawn plotter
(CX-4800, Itoh Electronics, Japan) tracings.
Comparative measurements were performed
at 80- 90% of maximal tension, since further
stretching lead to spontaneous contractions a n d
damage of ADR muscles. I n that range there was
little dependence of contraction times o n initial
passive tension3 SO that reliable average times
could be obtained.
I n the case of ADR muscle, measurements using stimulation at frequencies 2 1 0 Hz could only
be performed to a limited extent, since the aftercontractions to be described lead to irreversible
deformations and weakening of the muscle.
Electromyography (EMG) was
performed using stainless steel wires (+I 50 p,m)
insulated to the tip (California Fine Wire Company, Grover City, CA) and a Grass P15 preamplifier with band pass filters set at 0.3- 10 kHz
(Grass Instrument Company, Quincy, MA).
Electromyography.
T h e antiarhythmic d r u g tocainide (a
lidocaine derivative) was a gift from Astra-Werke,
WedeUHolstein, FRG. When animals were to be
treated once, 90 o r 20 bg/g tocainide were administered by i.p. or i.v. injection, respectively. For
continuous treatment, mice w e r e fed ad libitum
with reconstituted pellets containing 1.5 mg/g
tocainide.
Tocainide.
Care 8nd Experimental U s e of Animals. T h e care
and experimental use of animals were in accor-
434
Myotonic Mouse Muscle
dance with the German laws for the protection of
animals and the guidelines of the German Research Council. An approved petmit for animal
experimentation had been obtained from the local
authorities.
Muscles were frozen in melting
isopentane aild stored at -70°C until used. Cryostat serial sections (8 pni) were stained for either
succinate dehydrogenase” (SDH, EC 1.3.99. l ) , aglycerophosphate dehydrogenase’’ (GPDH, EC
1.1.99.1) or Ca2+-dependerit myosin-A’ll’ase (EC
3.6.1.3) after preincubation at p H 4.60 for 2-5
Stained sections were dehydrated in
alcohol and xylene and embedded in “Entellan
neu” (Merck, Darmstadt, FRG).
To determine numbers and relative areas of
fiber types, fibers were classified as type 2 glyc (in
contrast to type 2 ox) by the following criteria:
medium to low level of SDH staining, high level
of GPDH staining, and large diameter (cf. Fig. 4).
To determine the relative areas, outlines of fibers
were cut out from enlarged photoprints, and the
paper weight was taken as a measure of the area.
Histochemistry.
RESULTS
T h e tensions generated by single twitches of anterior tibial muscles from 10-20-day old ADR mice were
comparable to the wildtype controls. In 60-day
old ADR muscles with masses averaging 70% of
that of the wildtype controls, absolute twitch tensions were reduced to 60%. Up to the age of 60day, the time course of the twitch in ADR mice
was nearly identical to that in controls (Fig. 1, inset); only in older animals there was an increase of
the time to peak (not shown) and half-relaxation
times (Fig. 1).
Contractile Properties- Single Twitches.
Response to Repeated Stimulation. Occasionally
single twitches in ADR muscle lead to prolonged
after-contractions. After-contractions were regularly observed when ADR muscles were stimulated at 2 1 0 Hz, a n d this abnormality was nianifest already at 10 days postnatal (Fig. 2a). T h e
after-contractions of ADR muscle were more pronounced when an i n ~ o m p l e t e ‘o~r complete tetanus (Fig. 2c) was elicited but were not found in
wildtype control (Fig. 2b and d ) mice. After-contractions were also observed in the isolated ADR
soleus muscle (Fig. 2f). With low frequency stimuli, the maximum tension developed during the after-contraction often exceeded the highest tension
directly caused by the stimulus (Fig. 2e and f).
MLJSCLE & lvERVE
May 1988
-4 15
v)
E
L
1 :n.
--..
-...- 0
I
t
20ms
=
0
I
[
0
:I
,
a 0
.c
0
,
,
,
conditions (Fig. 2e). After-contractions in ADR
muscle are therefore independent of end plate potentials.
When an ADR anterior tibial muscle was denervated 3 days prior to the physiological measurements, the amplitude of after-contractions
was reduced to 24%. This unexpected behavior
has been described for chemically induced myotonias (cf. Ref. 22).
ADR
wT
,
,
,
t
t
0
0
Q
,
,
,
10 20 30 LO 50 60 70 80 90 100
a g e [ d I-
FIGURE 1. Single twitches and their age dependence of half-relaxation times of ADR and wildtype anterior tibial muscle. Inset:
single twitches with normalized maximum tensions. ADR and
WT, 60-day-old males. Half-relaxation times: each symbol represents an average of 10 twitches obtained from one individual;
lower ends of bars indicate the shortest times measured.
Since in the
isolated muscle the nerve endings could still release transmitter, the role of the nerve was tested
by curare treatment. In an ADR anterior tibial
muscle, the neuromuscular transmission of which
had been blocked to >9.5% (Fig. 2e, inset), a direct stimulus of 20 Hz provoked an after-contraction of the same amplitude as under standard
Role of Nerve in After-Contractions.
WT
Electrical After-Activity. Simultaneous recording
of EMG and contraction showed runs of muscle
action potentials during the time period of the after-contractions (Fig. 3a). Such runs were not observed in wildtype control muscle under identical
conditions (Fig. 3c). Upon cooling ADR muscle
from 35 to 20°C, mechanical and electrical afteractivities were prolonged to the same extent, by a
factor of about 2 (Fig. 3b).
In ADR mice
treated with tocainide, normal muscle relaxation
was restored within 5 minutes after i.v. injection,
30 minutes after i.p. injection (cf. Ref. I), and
2-3 hours after feeding the drug. Feeding of tocainide containing food pellets was used for a
Physiological Effect of Tocainide.
ADR sol
A
FIGURE 2. Tension response to repeated stimulation as indicated at baseline. (a,b) M. tibialis anterior of 10-day-old males:
a, ADR (body weight 5.6 9); b, WT A2G (6.0 9). (c,d) M. tibialis
anterior of adult males, stimulation with 0.2 msec pulses at 100
Hz: c, ADR (55 days, 18 9); d, WT (60 days, 23 9). (e) Effect of
curare on the contraction of an ADR (female, 65 days, 13.6 9)
anterior tibial muscle. Inset: force amplitude after indirect (0)
and direct ( 0 ) stimulation during superfusion with 0.1 mM
curare. Main trace: response of the same curarized muscle (at
10 min treatment) to a direct stimulus. (f) Tension response of
an isolated ADR (female, 70 days, 18 9) soleus muscle. Bar:
horizontal, 250 msec; vertical, in a,b, and f 10 mN, in c,d, and e
50 mN; e inset: 5 minutes, 50 mN.
Myotonic Mouse Muscle
5s
0 L rnVI
;I-
+-FIGURE 3. Simultaneous recording of mechanical (upper tracings) and electrical (lower tracings) responses of anterior tibial
muscle to tetanic (100 Hz, 0.5 second) stimulation. (a) ADR
(male, 70 days, 17.2 9) recording at 35°C (b) Same muscle as
in a at 20°C. (c) Wildtype control (A2G male, 80 days, 26 g) at
35°C (d) ADR (male, 120 days, 22 9) treated with tocainide for
100 days, at 35°C.
MUSCLE & NERVE
May 1988
435
long-terni treatment of the ADR syndi-onie. At
the end of a 100 day treatment, muscle relaxation
was nornial, and no electi-ical after-activity was observed by EM<; (Fig. 3d). When the treatnient was
discontinued, the rnyotonic behavior of the ADK
animal returned within 1 day, arid electrical and
mechanical after-activities were again recorded.
Enzyme Histochemistry. s l o w and fast muscle fibers caii be distinguished on the basis of the pH
stability of their myosin ATPases; slow, “type
1,” fibers being characterized by a11 acid stable
AI‘Pase, and fast, “type 2,” fillers by ail acid labile
ATPase.‘ Superimposed oii the myosin-ATPase
fiber types is a continuum of metabolic pheiiotypes, ranging from oxidative (ox), o r “red,” to
glycolytic (glyc), o r “white.” Although type 1 fibers
ar e always oxidative. type 2 fibers may display oxidative, intermediate, o r glycolytic metabolism. I n
most limb muscles of the wildtype mouse, the pattern of‘ fiber types is doniinated by fhst (type 2) tibers, 2.50% of which a re large diameter glycolytic
(type 2 glyc) fillers. .I’hese are characterized by
low levels of SDH (Fig. 4b anti d ) a nd high levels
of GI’DH (Fig. 4 f ) . In contrast, the anterior tibia1
muscle of the ADK nioiise was uniformly high in
SIIH (Fig. 4b and d ; pl‘able I ; cf., Refs. 28 and 29)
and low i n GPDI1 activities (Fig. 4e). This shift t o
an oxidative phenotype w i t s ohserveti in the EDL,
gastrocnemius. vastus, biceps, a n d triceps muscles
(Table 1). I n fast ADK limb muscle a nd in the soleus, ATPase staining re \ mle d a moderately reduced proportion of type 1 (slow) fibers (Fig. 3g
an d 11; Table 1 ) . In all these muscles, t h e w was no
indication of fiber atrophy o r regeneratiori.‘:’
In order to find out whether the metatx)lic abnormality of ADR muscle is confined to liint) muscle o r is a generalized phenonierion, several trunk
muscles were analyzecl by SDH and A’I‘Pase histochemistry. Some muscles that show a unifbrm oxidative fiber t y p e in the wildtype mouse, like the
tongue, showed no diff‘erence in the mutant. O n
the other hand, the typical absence of glycolytic fibers was evident i n ADK muscles loiigissinius
dorsi (Fig. 5a and d ; Table 2), pectoi-alis, and sternocostalis (cf. Kefs. 1.5 aiid 16). Some SDH fiber
heterogeneity was retained in two muscles involved in respiratioii: M. intercostalis and the diaphragm. With the histochemical stainings used,
no change was seen i n the heart.
ADR
WT
FIGURE 4. Enzyme histochemistry of ADR (a,c,e, and g) and
WT (b,d,f, and h) muscles from 80-day-old animals. (a,b) Overview of cross-sectioned anterior tibial muscle stained for SDH
activity. (c-f) Serial sections in the same orientation from comparable areas of anterior tibial muscle. (c,d) Stained for SDH
activity. (e,f) Stained for GPDH activity. (g,h) Borderline between M. soleus (to the right) and M. plantaris (to the left). Type
1 fibers appear dark in the staining for myosin-ATPase after
acid preincubation (pH 4.6). Examples of large glycolytic fibers
and type 1 fiber are marked in d,f, and h, respectively. Bar: 1
mm in a and b, 100 k m in c-h.
Effect of Tocainide on the Biochemical Phenotype.
I n ADR mice treated with tocainide for 100 days,
436
Myotonic Mouse Muscle
MUSCLE & NERVE
May 1988
After-contractions of skeletal muscle could be
due to any one of the following abnormalities:
centrally caused spasms, spontaneous muscle fiber
action potentials, contractures, o r a defect in the
relaxation mechanism. The latter possibility was
suggested by the strongly reduced content of
ADR muscle in parvalbumin (PV),” for which a
role had been suggested in the relaxation of fast
skeletal muscle.8
The increase of force during after-contractions of ADR muscle and the fact that after-contractions are also observed in the soleus muscle,
(the PV content of which is also low in the wildtype) argue against the ADR syndrome being due
to a relaxation defect caused by a lack of PV.
Since the oxidative-glycolytic character25 and
PV content“ of muscle are subject to modulation
by neural influences and muscle activity,20we suggest that the biochemical changes observed in
ADR muscle2G327
are consequences rather than
the cause of the contractile hyperactivity. An indication that the reversion of the biochemical phenotype might be possible is seen in the reappearance of glycolytic fibers and in the elevated PV
content of fast ADR muscle upon long-term treatment with tocainide. A similar reversion of the oxidative phenotype by treatment with a membrane
stabilizing drug has been reported for mouse
dystrophy3’ in which the muscle hyperactivity is
probably due to a motor nerve defect.5
T h e EMG data of this aper and the results of
intracellular
strongly support the
hypothesis that the ADR syndrome of the mouse
is a myotonia. The salient features of the ADR
myotonia are independence of the after-activity
from neuromuscular transmission, the electrical
after-activity, and the fact that both after-activities
can $zz,suppressed by a membrane-stabilizing
drug.
The physiological characterization of the ADR
syndrome as a myotonia has led us to genetically
Table 1. Fiber type compositions of ADR and WT muscles.
Muscle (age)
Fiber type
ADR
WT
TA
I
3.2 f 0.4%
2 glyc.
(n = 2)
0Yo
1.9 f 0.9%
(n = 3)
44.0 f 2.2%
(n = 4)
0.4 f 0.4%
(n = 5)
50.0 f 7.5%
(n = 5)
71 .O f 11.O%
(n = 6 )
0.05 t 0.09%
(n = 3 )
(15-18 days)
1
TA
(80 days)
2 glyc.
Soleus
(80-95 days)
1
2 glyc.
(n = 2)
0.3 2 0.3%
(n = 4)
0Yo
(n > 10)
47.0 t 5.2%
( n = 5)
0%
(n = 2)
Note. Percentages of the fiber types 5 standard deviations (n = number
of animals) are given; for n = 2, the range of values is indicated. For a
definition of the fiber types, see Fig 4. In the 80 day W T tibialis anterior,
the contribution of 2 glyc fibers to the cross-sectional area was 68%.
Note the complete absence of 2 glyc fibers from ADR fast muscles.
the oxidative phenotype of the anterior tibia1 and
the longissimus dorsi muscles was partially reversed to normal (Fig. 5b and e; Table 2).
DISCUSSION
The uniformly oxidative, type 2 ox-like phenotype of ADR muscle is not a nonspecific consequence of neuromuscular disease, since a different phenotype was observed in other mutants like
the wobbler (WR) mouse and motor endplate disease (MED).24It should be noted, however, that
some biochemical features, like elevated levels of
SDH’8’21325and a reduction of parvalbumin
content,12 are observed, albeit to a lesser degree,
in muscle from the dystrophic (DY?’) mouse.
The distinctive feature of the ADR muscle is
its response to repeated stimulation by nerveindependent after-contractions. This physiological
behavior is not found in muscle from WR, MED
(Reininghaus, unpublished), autosomal dystrophic
(DY, DY‘J), termed “myotonic” in Ref. 5), or Xlinked dystrophic (MDX)4 mice.
recording^"^'^
Table 2. Effect of tocainide treatment on fiber types in longissimus dorsi muscles of myotonic and normal mice.
100 days tocainide
Untreated
Fiber type
1
2 glyc
ADR
WT
ADR
WT
0.75 t 0.05%
(n = 2)
0%
(n = 3)
6.4 f 1.6%
(n = 2)
62.0 2 3.0%
(n = 4)
0%
(n = 2)
76.5 -t 1.5%
(n = 2)
2.9 f 1.0%
(n = 2)
65.5 k 1.5%
(n = 2)
Note Percentages of fibersgiven as in Table 7 in untreated wildtype longissirnus dorsi, the contribution to the cross-sectional area of type 2 glyc fibers
was 86% Experimental conditions were as given /n Fig 5 Ages of mice analyzed tocainide-treated mice. 122-133 days (treatment for 700 days),
untreated mice, 60-95 days
Myotonic Mouse Muscle
MUSCLE & NERVE
May 1988
437
FIGURE 5. Effect of tocainide long term treatment on ADR muscle. Cross section of longissirnus dorsi muscles stained for SDH activity.
(a,d) 60-day-old ADR; (b,e) 133-day-old ADR after a 100 day tocainide treatment; (c,f) 60-day-old WT. In untreated WT and ADR mice,
the SDH phenotype of muscle does not change between 40 and 2150 days postnatal. Bar: 500 pm in a-c; 150 pm in d-f.
identify adr and an independently arisen mutation, “myotonia” (adrmrO,formerly nit””), as
allelic. The only report on the contractile behavior of MTO muscle shows after-contractions but
claims that these can be suppressed by curare.6
This would be at variance with our results on
ADR muscle. However, the three known alleles of
the gene “motor endplate disease”24 show that
’’
qualitatively different phenotypes may arise from
independent mutations at the same genetic locus.
Note Added in Proof. T h e claim“ that aftercontractions in the MTO mouse are curare sensitive has been refuted by recent results comparable
to those shown in Fig. 2e (Reininghaus, unpubl.).
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