寡運動がジストロフィーマウス腓腹筋の収縮能と組織化学的特性に与える影響

理 学 療 法 学　第16巻 第1号　 11

−

17頁 （1989年）

Effect

　

of

　

Hindlimb

　

Suspension

　

on

　

Young

　

and

　

Adult

　

　

　

　

　

Gastrocnemius

　

Muscle

　

in

　

Dystrophic

　

Mice

＊

Nobuhide

　

HAIDA

　_and 　

Katsuhiko

　

TACHINO

＊亊

ABSTRAGT

　

Disuse　atrophy 　induced　by　Iimb

−

immobilizationエeportedly 　protects　

dystrophic

　IIlouse　muscle

froln　histopathological　cllallges

．

　This　experilllen亡was　conducted 　to　determine　whether 　disuse

atroph _アinduced　by　hypokinesia！hypodynamia （H！H）

_．

limits　the　

histopathology

　and 　contractile abnormalities 　typically　observed 　ill　the　dystrophic　mouse

．

　Two 　weeks 　of　HIH 　suspensiol ユ was

induccd　in　16　Line　129B6FI　dystごophic 皿 ice　at　tw｛｝ages

，

4weeks _（8　micc _）and 　I2　weeks _（8　mice_）

．

F洫 een 　untreated 　dystrophic　mice 　served 　as　controls

．

　In　genera1

，

　HIH 　exaggerated 　the　dystrophic

symptoms

，

　especially 　in　the　

younger

　mice ；it　reduced 　animal 　weight

，

　muscle 　weight

，

　maximum

twitcll　and 亡etanic 　tensic）n

，

　and エate　of　twitch　and 　tetanic 　tcnsion　developmen

．

t

，

　HIH 　reduced

thc　size　of　type_l　alld　type 　

2

　fibcrs

，

　increas¢d　the　_percentage　of　type_l　fibers

，

　and 　decreased　the

perc∈ntage 　of　ty蔓）e　2　丘

bers

　

in

　

both

　

young

　and 　adult　muscles

・

　H ！H　did　not　alleviatc 　the　fiber

size　variability

，

　degree 〔｝f　necrosis

，

　central 　nuclcation

．

　infiammatio

．

n

，

or エnuscI

 丘brosis　in　d_＞

・

strophic

muscles

．

　 Thc　data　demonstratc　that　disuse　by　HIH 　does　not　

prevent

　the　histopathological

deterioration　or　loss　of　luuscle　

function

　in　

6

　and 　I4　week 　old　dystrophic　mice

，

　 TIlis　suggests that　

physical

　interventions　which 　

prevent

　muscle 　deterioration　lnust 　be　applied 　to　immature   usclCS

，

　_PTi・r　t・ ・nset 　of　necr ・sis

・

Key 　words ： Suspensionhypokinesia

・

Gastrocnemius

・

Dystrophis m （）usc

IntrodUC 直on

　

Disuse

　atrophy 　

has

　reportedly 　alleviated 　muscle

histopathology

　

in

　

animal 　models 　of　muscu 正ar

dystrophy1

〕

−

5〕

．



Several

methods 　

have

　

been

　

used

to　experimentally 　

induce

　

disuse

　atrophy 　

in

　nor

一

皿 al　 animals ：

limb

　immobilization ，　 tcno 亡omy

，

proIonged

　

general

　anesthesia

，

　small 　cage 　restraint

・

surgical



isolation



of



the

_lumbosacrai

cord ・ and

hindlimb



suspension

_hypokinesia

！

hypodynamia

＊

寡運動がジ_ス トロ フ _ィ

ー

マ ゥス_{腓 腹 筋}の収縮 能と組 織 化 学 的 　　特 性に与え る影 響

＊＊ _{灰 田信 英}

，

_{立 野 勝 彦}：_{金 沢木学 医療 技 術 短 期 大 学部}理 学 療 法

　　学科

　　Depart皿 ent 　of 　Physical　Therapy

，

　School　of　 A正1藍ed

　　

Medical

　Professions

，

　Kanazawa　Upiversity

　　（Received　14　Apri口 988）

（HIH

）

6）

−

13｝

・



_However

_，

　 only

_limb　i

皿 mobiliza

−

tion3 ）

・

4） _{and 　muscle 　tenotomy1} ）

，

4）

・

5）_正lave

been

studied 　

previously

　as　

potential

　

tllcrapeUtic

　

phys

三

一

cal　 interventions　

in



dystrophic

　animals

・

One

dif

丑culty　with 　

both

　of　these　methods 　

is

　that　they

prevent

　

freedom

　of 皿 ove_皿 ent

・HXH

　suspension

，

on 　the　other 　hand

，

　

permits

　the　hindIimb 　

Ipusclcs

to



undergo



a

_full



range



of



voluntary



isotollic

contractions 　 and 　mainta 三n 　tlleir　normal 　resting

lengths

．

　The

　object 　of　this　study 　was 　to　evaluate 　whether

HIH

　

has

　a　

beneficial

　effect・nthemQrphometric

，

histologic

，

　

histochemical

　and

．

　contractile 　

proper・

ties　of　

gastrocne

皿

iUs

　muscles 　

ln

　

young

　and 　adu 正t

12

E*twza\

Materials and Methods

Dystrophic

(dyfdy)

mice of the strain

I29B6FYJ

were used. HIH'was

induced

in

16

dystrophic

mice

beginning

at two different ages,

4

weeks

(8

mice) and l2 weeks

(8

mice),

Seven

and 8 untreated dystrophic mice at 6 and l4 weeks, respectively, served as controls

(CON).

Mice

were

subjected to H/H using an apparatus modified

from

that originally

described

by

Moreyi3).

The

mice were suspended so that their

hindquarters

-vere not

bearing

Ioads fora

_period

of two weeks, using a

body

harness

and swivel in a slightly

head-down

tiltthat

barely

_prevented

the

hind-linibs

from

contacting any supporting surface,

Free access to

food

and water was

_permitted

by

use ef the

ferelimbs

on a

_grid

surfaced

fioor.

After

two weeks of suspension the mice were

sacrificed

(at

age

6

or

14

weeks)

b>r

cervical

dis-Iocation.

Muscle$

were

dissected

for

contracti]ity studies, and contralateral medial

_{gastrocnemius}

(MG)

muscles were

frozen

in

isepentane

cooled

in

liquid

nitrogen

for

histological

evaluation.

Muscle

length

_(Le)

was measured at the

_point

at

"rhich

the

isometric

tetanic

force

was maximum

prior

to evaluation of contractile

_properties.

Following contractile experjments, blotted wet weight

(LVT)

was measured and cross-sectional

area

(CSA)

calculated as

LolX･VT.

Isometric

con-tractile

_preperties

were assessed on

isolated

gastro-cnemius muscles. These were

_placed,

immediate-ly

after sacrifice,

in

a

50rn1

double-walled

350C

bath

with aerated

(95%02,

5%COe)

Kreb's

Ringer

solution and tubocurarine

_SxIO-5

_grnfinl,

Stimulation

was appljed using two

_platinum

wire

electrodes and supramaximal square wave

_pulses

from

a stimulator

(Nihon

Kohden, model SEN

2101).

.

Stimulation

parameters

were:

frequency

240

Hz,

pulse

duration

1

ms, and train

duration

280ms

with 2 minute rest

intervals.

Tension

_parameters

included:

rnaximum tetanic tension

(Po),

single

ag16U

rg

1

_e

twitch tension

(P),

maximum rate of tetanic

(dPofdt)

and twitch

(dPfdt)

tension

development,

maximum rate of tetanic

(-dPo!dt>

and twitch

(-dPfdt>

tension relaxation. The time

ters

included:

contraction time

(CT)

(time

from

stimulus tomaximum twitch tension);txvitch lf2

relaxation tirne

(If2

RT)

(time

from CT to 112

relaxation of the twitch); tetanic

I12

RT

_(time

from

end of tetanic stimulus to

lf2

relaxation of the tetanus>.

To

test

fatigue

resistance, tetanizing trains oi stimuli were

qelivered

at a frequency of

O.2sec,

for

five

minutes. This

cliallenge

has

been

shown to exceed the energy supply mechanisms

ef normal muscles to recover

from

the effect of

preceding

worki4).

The

fatigue

resistance

(%

Po)

is

the

_percent

ef

the

tension

irom

the

final

stimulus as compared to tension

developed

by

the

initial

tetanic stimulus.

The

MG

from

the contralateral

Iimb

was

frozen

and sectioned at

8

ptm.

The

sections were stained

with myosin

ATPase

(pH=4.8,

4.6

and

9.4>

and

hematoxylin ancl eosin

(H&E>i5).

Staining

for

myosin ATPase identifiedfast-twitch,type

2

fibers

(alkali

stable) and slow twitch,type

1

fibers

(acid

stable)i6), O..uantitative

histograms

of fiber

cross-sectienal area were obtained with an image

pro-ce$sing s}rstem

(Nihon

Kohgaku,

Cosrnozone

98).

Quantitative

analysis of the

morphologyfpatholo-gy

was

performed

from

the sections stained

for

H&E

using amodified by Dubowitz and Brooke17).

Significance

was accepted at

_p<O.05.

All

values are expressed as mean ± standaTd deviatien.

Results

'

MorPhometric measurements:

Animal

weight,

muscle wet weight and

CSA

were

lower

in

ex-perimental

mice

<DYS)

than

in

CON.

HfH

reduced DYS

body

weight at

6

and

14

weeks

by

1891i and l7%, respectively

(15.4

±

l,eg

for

6

week CON, Il.7±

O.8g

for

6

week }I/H;

l6,7

±

O.6g

for

14

week

CON,

and

14,8

t:O.9g

for

14

HypokinesiafHypodynamia

on

Young

and

OId

Table

1

Morphometric

measurement

Muscles

13

6weeks 14 weeks

Control(n-D Suspensien

(n-8)

Control(n-8)Suspension

(n

--

8)

Anirnal

Weight

_(g)

Muscle

Wet

Weight

(mg)

Muscle Wet Weight!Animal Weight Muscle

Cross-Sectional

Area

_(mm2)

15,4±2.6

108.0

±

28.4

7.0:.e1,3 8.1±

L3

11.7±2.1* 74.3±

19.4*

5.8±1.7 5.9±1.4* 16.7± 1.6

242.7

±

,

58.3 14.5±3.1 16.9±3.7 14,8±2.4

194,3

±

52.2

14.1±4.5

15,5

±

,

2.8

Values

aremeans ±

S.

D.*<O.5

Table 2 Size andpereent of

dystrephic

fibers

6 weeks 14weeks Control(n:=7)

Suspension

(n-8)

Control(n==7)

Suspension

(n-8)

Fibersize type 1 type 2 Fiber

_%

type 1 type 2

(ltm2)

1,853±632 887± 538 10.4±4.4 89,6±11.7 1,028±588* 485±

,

323* 19.3±8.4*

81.7

±7.7 1,167±526 763±395 15.4±7,1 84.6±9.3 1,127±528 761±413 21.7±5.9 78.3±

5.9

Values

aremeans ±

S.D.*<O,5

40302010 403020

10

403020 10o .

/

_×

6wk-CONOType 1 eType 2

x

x

'o--..nN.-s

_.. Ach><vasAHJ:tsp-pt. ×

'

×

6wk'HfH ./e"

×

, , ･/x . o/e'S--o 14wk'H!H

×

xg==

:6 Fig.1 5

10

15

20 25 30

Fiber

size

("m2),

× 100

Distributionof type1and type

'2

fiber

popu-lations

in mouse medlal _{gastrocnemius}

muscles.

'

'

muscle weights

decreased

46%

and

25'%

after suspension. HfH

decreased

the.mean

CSA

of

6

week muscle

fibers

by

27%,

but

did

not alter

CSA in ll week muscles.

Jlistochemical

evalttation: Fiber type and size

distTibutions

are summafized

in

Table

2

and

Fig,

I. Suspension resulted in significant

reduc-tion

_in

size oE

both

type

l

and type

2

fibers

in

the 6week MG. Type I

fiber

size

decreased

55'%

and type

2

fiber

size

decreased

54'9C

compaTed to

CON,

but

55%

and type

2

fiber

size

decreased

54%

compared to

CON,,but

not

decreased

signifi-cantly

in

14

week muscles.

Suspension

induced

a significant increase in the

_percentage

of type

1'fibers

_(from

10%

to 19%

for

6

week

MG,

and

from

15% to

22%

for

the 14 week' MG) with a

parallel

decrease

in type

2

fibers.

HistoPathological

findings:

Fiber

abnormalities were not alleviated

by

HfH

regardless ef age

(Tab]e

3),

H!H

induced

atrophy

did

not

_prevent

er reduce muscle

degeneration

(as

_quantified

by

14

gg*tsza\

(percent

of

basophilic

fibers)

increased

in 14week

MG, and did not change

in

the

6

week MG.

Phagocytosis

and

inflanimatory

cells

increased

in

the l4 week muscles and decreased in the 6 week muscles.

The

_percent

of

fibrosis

was

increased

in

14 week MG, but no change was observed in 6

week MG

by

H/H.

.

Contractile measurements:

(Table

4)

HIH

ex-acerbated the

_dystrophic

characteristics. It

pro-longed

the

twitch

1/2

RT

of

6

and 14 week

MG

tt

'

Table 3 Incidenceef

fiber

abnormallti-es in

control and suspended muscles

rg16tsee

1

_g

6weeks 14

Cont-

Suspen-

Cont-rol sion ro!

APAP AP weeks sion

AP

Fiber splitting

Necrosis

FibrosisPhagoeyto$is

Inflammation

Basophilia

Number

of mucles o2111277566656132258275663133524875536412o2118768677

A

:Absent, P :Present

Table 4 Contractilevariablesfor suspended

by

49%

and 4S%, respectively,

H/H

_prolonged

the twitch contractile time at

6

weeks

by

81%,

but

14

week muscles were not changed

by

HfH.

In addition, the tetanic

_lf2

_RT

of

the

6

and l4 week muscles

increased

18%

and

l8%.

HXH

significantly reduced

_gross

tetanic tension

(Po)

and twitch tension

(P)

at

both

ages.

The

reduc-tion in

Po

was still evident when adjust. for

cross-sectional area

(CSA).

PefCSA of the

₆

and

l4

week muscles was

reduced by 48% and 64%, respectively. Thus,

the

loss

in tetanic tension was

_greater

_than the

loss

of muscle CSA. HIH accentuated the already

increased

fatigue

resistance of

_young

dystrophib

muscles, although

it

did

not alter

the

fatigue

resistance oE the older muscles.

HIH

reduced the rates of tension

development

and of relaxation.

It

reduced the rate of twitch tension development

_(d?fdt)

of the

6

and 14

week muscles

by

55%

and

48%,

respectively.

Similarly,

HfH

reduced the rate of tetanic tension development

(dPofdt)

of 6 and 14 week

rnuscles

l)y

59%

and

540/.,

respectively.

The

rate

ef twitch relaxation

(-dPldt)

of the

_young

and

and control _{gastrocnemius}

'

6 weeks 14weeks

Control(n=OSuspension

n=8

Control

(n=8)

Suspension

(n==8)

Twitch time Parameters :

Contractiletime

(rnsec)

Rate of tetisiondevelopment

(gm/sec)

Rate of relaxation

(gm/sec)

HalfLrelixation

time

_(rnsec)

Tetanu$ Time Paramaters :

'

Rate

of tension

development

_(gm7$ec)

Rate

of relaxation

(gm/sec)

Half-relaxation

time

_(msec)

Tension and Fatigue: Twiteh tension

_(gm)

Twich tenslon/rnuscle cross-sectional

area

(gm/mm2)

Tetanic tension

(gm)

'

Tetanic

tensionfmuscle cross-sectional

area

(gm/mm2)

Fatigue resistanee

(%

Po)

10.5± 1.3 168,O±75.1 55,8±

25,4

10.6±1.3 316.4±115. 518.0±217, 29.2±2.4 12.1± sls 1.49±O.67 150.2±59.e 18.5± 5.6 49.2+6.3 9o 13.8±2.6* 75,6±24,9* 27.4±7.9* 15.8±4.5* 129,2± 34,4* 110.8±48.7 34.4±6.9 7.1± 3.4* 1.38±

,

O.69 57.6÷

.

I4.8*

9.7 ±3.4*

s3,2

±22,2* 11.8±2.6* 138[O±39,2 43.0±12.2 12.5si2.4 271,6±67.7 444.･4±136.5 31.3 ±2.6 23,5± 4.0

1,39

±

,

O.32

310.0±

,83.3

18.5±3.2 61.2±

10.6

13.8±2.6 72.0±44.4*

23.8

±

10,1*

17.9±4.5* 124.0±78,3* 109.6±65.1* 35.4±5.6 16.0±10.1

O.89+O.58

203.9±57,7 6.7±3,7* 65.0±7.7

Hypokinesia/Hypodynamia

'

old muscles decreased

51'%

and

45'%,

respectively.

The rate of tetanic relaxation

(-dPofdt)

oE the

young

and old muscles

decreased

79%

and

75%

of control values, respectiyely.

'

Discussion

'

HIH exacerbated, rather than aineliorated, the

dystrophic

symptoms.

Both

the

6

and

14

week

muscles

became

weaker, slower, and more

fatigue

resistant as a resu]t of

HIH.

However,

HIH

had

ti

_greater

effect on

_younger

mice

than

on older

ones.

It

is

not surprising that

6

week muscles

becam,e

weaker

following

suspension, as

there

was a significant

loss

in

muscle weight,

CSA,

and

atrophy of both type 1 and type

₂

fibers,

Itwas

surprising,

however,

that

_HfH

reduced maximal

tension

in

the

I4

week muscles, without signifi-cantly altering muscle or fibercross-sectional area.

Whereas

previous

studies of

limb-immobiliza-tion

(with

other methods) shewed a reduction

in

the

histoPathology

of

dystrophic

muscle,

HIH

did

not

induce

improvement,

H!H

did

_produce

severe atrophy,

but

did not

_prevent

or Teduce muscle necrosis at either age. This is

_quite

different

ftom

other studies, with very _young

129

Re-J

mice using either

joint

fixation

or

tenotomy3),4),5).

The

differences

between

our results and those of others may be related to ages

and strains ef mice, methods used to

induce

disuse, or a combination of these factors.

This

study used the

129B6Fl

hybrid,

a cross

between

the

129

Re-J

and

C57

BL16J

inbred

strainsi8).

The

l29

Re-Ji9)

and

C57

BL16J20}

mutants

do

not hFve

identical

_phenotypes

and

show considerable

,variation

in

histologic

and contractile characteristics.

Slow-twitch

muscle and oxidative

fibers

are more affected

in

the

C57

BLf6J

mice2i)r24), whereas

fast-twitch

muscle and

glycolytic

fibers are more affected

in

the 129

Re-J

strain2i)T25)L28).

Although

tlie

l29B6Fi,

hybrid

is

_quite

similar to t,he l29

ReJ

mouse,

The

hybrid

is

healthier,

with an

increased

life

on Young and

Old

Muscles

15

span and a

growth

rate closer to that of a normal

mouse29).

The

inability

to

prevent

muscle

fiber

ation in _thisstudy

_4s

compared to _other

gations

is

probably

due

to the.age

differences:

four weeks of age

followed

by two weeks of

suspension

in

thisstudy versus one week of age

followed

by

two weeks of

joint

irnmobilization

or

tendon transection

in

other

investigations.

In

129

Re-J

DYS

mice, there

is

normal

development

during the early

_postnatal

_period

followed

by

severe

_progression

of the

disease

duting

the

'

second week of

life.

_During

_{the third} week the muscle rapidly

degenerates,

stabilizes

between

the

fourth

and eighth

_postnatal

weeks, and then

general

atrophy and

de-differentiation

of

chemical _profilesensue4].

Other

studies showed that

disuse

atrophy was

effective at

preventing

some of the

dystrophic

histopathology

when the

intervention

were started

before

and continued

during

the rapid

sion of

the

disease.

In

contrast, our methods, and

disuse

atrophy

_produced

by

tendon transection

in

8-12

week old･mice, failed to reduce fiber

hecrosisi>.

This

suggests that only

intervention

before or

during

the rapid

_progression

of

the

disease

is

effective

in

reducing the

_pathology.

It

has

also

been

pToposed

that small-caliber

fibers

pToduced

by

disuse,

denervation

atrophy, or

growth

hormone

deficiency

might

impart

ty to necrosis

in

dys'trophic

mice,

hamsters

and

chikens30).

Our

data

show that reduction of

fiber

size

by

intervention

as early as

four

weeks,

(which

is after th'e histopathological symptoms

have begun to appear) does not

_protect

against

dystrophy.

This

is

probably

because

the muscle

had

already reached a critical stage of

ration".

Once

this occurred,

HfH

intervention

was not able to

inhibit

or reverse the expression

of the

dystrophy

as evidenced

by

weakness and

.

16

_mp#eslk$

Roferences

'

1> Wilson, B.W., Kaplan,

M.A.,

Merhoff, W.C. and

Mori, S.S.:InneTvation alld the regulation of

acetylcholinesterase activity during the

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Dubowitz, V., Sturugalska-Cynowska,

M.

and

Gallup,B,: Neural influencesinmuscle

_pathoiogy.

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3)

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pTession

of

_pathology

in

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'4>

Wirtz, ?.,Loermans, H.: Immobilization ef

trophic mouse muscle

_prevents

_pathology

and

necrosis of muscle fibers.Muscle & Nerve,6:

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5) Wirtz,P.,Loermans, H.: Research insupport of

tTeatment of muscular dystrophy in mouse, In

Kate, L.?.,Pearson, L,P.and Stadhouders,A.

(eds,)

Research

lnto

the Origin Rnd Treutment of

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_pp.

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6> Goldspink, D.F.:The

ii,fiuence

of

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7)

Musacchia,

X,J.,Devers,D.R.: A new rat model

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the structure and function of skeletal muscle.

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_Jaspers,

S.R.

Tischler,ME: Atrophy and _growth

failureof rat hindlimb muscles in tail-cast

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_J.H.,

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75-98,

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･

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Hypokinesia ／Hypodynamia 　on　Young 　and　

Old

　

Muscles

_ユ7 〈要 　 旨〉 寡運 動が ジス トロ フ ィ

ー

マ ウス腓 腹 筋の収 縮と組 織 化 学 的 特 性に与 え る影 響 　　　 　　灰 田信英 　立野勝 彦 金 沢大 学 医療技 術 短 期 大 学 部理学療法 学 科 　寡 運動 （

Hypokinesia

／Hypodynamia ）に伴 う筋 萎 縮が

，

ジス トP _{フ ィ}

ー

_筋の病 理 組 織 学 的 変 化並 びに筋 収 縮特

．

1

生に与える影 響につ い て検 索した

。

4週 齢 （若 齢 群 ）と12週齢 （成熟群）の 129B6F1 系ジス ト P フ

a

一

マ _ウス 31_{匹 をそ れ ぞ れ 実 験 群と対 照 群}に分 け

，

実験 群に対し て は

Morey

の tail　suspension モデル を

用いて後 肢 を 無 荷 重 状 態 とした

。

2週 間の寡 運動後

，

腓腹筋を採取し

，

湿重量測定後 myosin 　

ATPase ，

Hematoxylin

＆ Eosin _{染 色を実施 し}

_，

_{組織化学的 並 びに組 織 学 的 検 索を行} っ た

。

ま た合わせ て対 側 腓 腹 筋 の単 収 縮

，

強縮 張力か ら収 縮特性につ い て計 測した。 　その結 果

，

寡 運 動の影響は幼若ジス トロ フ ィ

ー

マ ウス 群に著しく

，

体 重

，

筋 重 量

，

単 収 縮 及び強 縮 張 力は 対 照群に_比べ _{減 少し た}

_。

_しか し組 織 化 学 的 変 化は若 齢 群

，

成 熟 群 共に腓 腹筋の タイプ

1

_型，

2

_型線維は 同 程 度に_萎縮し， かつ 1型 線 維の構 成 比 率の増 加が認め られた

。

病 理 組 織 学 的 所 見は

，

組 織 化 学 的変化と同 様1

・

C

．

若 齢群

，

成熟群共に_{筋 線維}の大 小不同がび漫 性に

，

さ らに 中心核

，

炎 症 細 胞

，

壊死 や結合織の増 殖 像が 同頻 度に 出現し た

。

　以上の結 果より

，

若 齢 群に見 られた変 化は

，

寡 運 動に伴 う成 長の

一

時 的 停 滞であり

，

ジス トロ フ ィ

ー

筋に 対 して本 法に よる寡運 動 性 萎 縮は病理学 的 変 化になん ら影 響を及 ぼさ ない_事が示唆さ れ た。