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Aging o he musculoskele al sys em : How he loss o es ogen impac s muscle s eng h
© 2019 Else ie Inc.
Accep ed e sion (Final d a )
Collins, B i any C.; Laakkonen, Eija; Lowe, Dawn A.
Collins, B. C., Laakkonen, E., & Lowe, D. A. (2019). Aging o he musculoskele al sys em : How
he loss o es ogen impac s muscle s eng h. Bone, 123, 137-144.
h ps://doi.o g/10.1016/j.bone.2019.03.033
2019
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BONE Special Issue: Musculoskele al Aging
Aging o he Musculoskele al Sys em: How he Loss o Es ogen Impac s Muscle
S eng h
B i any C. Collins1, Eija K. Laakkonen2, and Dawn A. Lowe3
1Depa men o Human Gene ics, Medical School, Uni e si y o U ah
2Ge on ology Resea ch Cen e and Facul y o Spo and Heal h Sciences, Uni e si y o
Jy äskylä
3Di isions o Rehabili a ion Science and Physical The apy, Depa men o Rehabili a ion
Medicine, Medical School, Uni e si y o Minneso a
Re ised_manusc ip _clean
Click he e o iew linked Re e ences
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Abs ac
Skele al muscle weakness occu s wi h aging and in emales his is compounded by he loss o
es ogen wi h o a ian ailu e. Es ogen de iciency media es dec emen s in muscle s eng h
om bo h inadequa e p ese a ion o skele al muscle mass and dec emen s in he quali y o
he emaining skele al muscle. P ocesses and componen s o skele al muscle ha a e a ec ed
by es ogens a e beginning o be iden i ied. This e iew ocuses on mechanisms ha
con ibu e o he loss o muscle o ce gene a ion when es ogen is low in emales, and
con e sely he main enance o s eng h by es ogen. E idence is accumula ing ha es ogen
de iciency induces apop osis in skele al muscle con ibu ing o loss o mass and hus s eng h.
Es ogen sensi i e p ocesses ha a ec quali y, i.e., o ce gene a ing capaci y o muscle,
include myosin phospho yla ion and sa elli e cell unc ion. Fu he de ailing hese
mechanisms and iden i ying addi ional mechanisms ha unde lie es ogenic e ec s on
skele al muscle is impo an ounda ion o he design o he apeu ic s a egies o minimize
skele al muscle pa hologies, such as sa copenia and dynapenia.
Keywo ds: Aging; Es ogen; Skele al muscle; S eng h
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In oduc ion
Skele al muscle weakness is an undesi able consequence o aging. Sa copenia, he
age- ela ed loss o muscle mass and s eng h, has been iden i ied as he c ucial p ecu so o
ail y, leading o disabili y, loss o independence [1], as well as hospi aliza ion [2] o aged
indi iduals. While dec eased muscle mass con ibu es o sa copenia, s eng h declines o a
g ea e ex en such ha s eng h no malized o muscle size is educed wi h age. Dynapenia is
a ela i ely new e m used o desc ibe his age-associa ed loss o muscle s eng h ha is
independen o muscle a ophy [3]. The signi icance o dynapenia is exempli ied by Visse
and Schapp, who conclude ha he loss o muscle s eng h consis en ly p edic s alls,
mo ali y and unc ional s a us, such as mobili y in elde ly indi iduals, while e idence o he
ela ionship be ween low muscle mass and hese ou comes is limi ed [4].
Skele al muscle o emales is dually a ec ed by age due o he simul aneous loss o
o a ian ho mone p oduc ion. In women, he p oduc ion o es adiol and p oges e one alls a
menopause, occu ing a 45-52 yea s o age [5, 6]. Declines in s eng h a e accele a ed a his
age in women [7-13] and me a-analyses o nea ly 10,000 pos -menopausal women showed
ha hose on ho mone he apy (HT) had sligh ly g ea e muscle s eng h han hose no on
HT [14]. Such esul s poin owa d es ogen as being he key o a ian ho mone a ec ing
muscle s eng h in women. In his a icle, we will use he abb e ia ion HT o encompass bo h
es ogen and combined es ogen-p oges e one he apy in women as ecommended by he
2017 No h Ame ican Menopause Socie y posi ion s a emen [15].
A sys ema ic e iew and me a-analyses compa ing o ce gene a ion o muscle om
o a ian ho mone-de icien and – eple e mice also indica e ha muscle s eng h dec emen s
occu when es ogen is de icien [14]. The mos common me hod o inducing o a ian
ho mone de iciency in p e-clinical oden esea ch is o a iec omy, i.e., bila e al su gical
emo al o he o a ies, and his app oach is o en e e ed o as a model o menopause [16].
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In oden s, es ous cycles become i egula and e en ually cease wi h age. The age a which
his occu s is a iable ac oss s ains o mice and a s. Fo example, cessa ion o es ous cycles
in C57BL6 mice was ini ially epo ed o occu be ween 13 and 16 mon hs o age [17] and
was mo e ecen ly measu ed o occu be ween 17 and 20 mon hs o age [18]. The e m
o a ian senescence is used o indica e when es ous cycles cease and his na u al, aged-
induced loss o o a ian ho mone p oduc ion is mo e simila o menopause in women han
o a iec omy su ge y ( e iewed by [19]). Despi e his mo e compa able physiology, he aged
emale oden model is in equen ly used o analyze how he loss o es ogen de imen ally
a ec s muscle s eng h.
The ocus o his e iew will be on he pu a i e mechanisms ha con ibu e o he loss
o muscle o ce gene a ion when es ogen is low in emales, and con e sely p ese e s eng h
when es ogen is p esen (Figu e 1). S udies on menopausal women and es ogen-de icien
and – eple e oden s will be summa ized as o how muscle s eng h is a ec ed by es ogen,
and lack he eo . The speci ic es ogenic mechanisms conside ed in he e iew will be limi ed
o 1) egula ion o skele al muscle mass a ec ed by es ogens and 2) p ocesses in skele al
muscle con ac ion, which i pe u bed by es ogen de iciency will diminish he gene a ion o
o ce.
1. Es ogen and skele al muscle mass
While he anabolic e ec s o and ogens on skele al muscle in males a e ecognized o
imp o e mass and hus s eng h (e.g., [20, 21]), by compa ison he e is much less known
abou e ec s o es ogens on skele al muscle mass in emales [22]. Cu en e idence indica es
ha es ogens ha e a ole in main aining muscle mass [23-25]. When es ogen is de icien , as
occu s wi h ad anced age in emales, muscle a ophy ensues and con ibu es o muscle
weakness. This sec ion o he e iew will p esen e idence on cellula and molecula

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mechanisms by which es ogen may con ibu e o main aining skele al muscle mass and on
he con a y, mechanisms unde lying how es ogen de iciency may cause a ophy. While age-
ela ed weakness (dynapenia) can occu independen o a ophy, i is impo an o no e ha
loss o muscle mass may also con ibu e o loss o s eng h.
Muscle p o ein u no e . Dys egula ion in muscle p o ein u no e du ing es ogen
de iciency wi h he balance ipping away om p o ein syn hesis and owa d p o ein
deg ada ion would con ibu e o ibe a ophy and hus o e all loss o muscle mass. The
e ec s o es ogens on basal, es ing skele al muscle p o ein u no e ha e been s udied in
women unde a ious condi ions o es ogen manipula ion ( o example in [26]) and
nominally in animal models.
Muscle p o ein syn hesis. Rela i ely mo e s udies ha e measu ed a es o muscle
p o ein syn hesis han deg ada ion as ela ed o es ogen s a us. Myo ib illa p o ein syn hesis
a es in p e-menopausal women did no di e be ween hose in ollicula (~low es ogen)
compa ed o lu eal ( ela i ely high es ogen) phase o hei mens ual cycles [27]. A
sho coming o his ype o s udy design is ha p oges e one luc ua es in addi ion o es adiol
( he mos bioac i e es ogen in non-p egnan adul women) and he e o e, delinea ing he
impac o es ogen e sus p oges e one on muscle p o ein syn hesis is no possible. S udies in
which deli e y o ho mones is con olled ci cum en his issue. Adminis e ing indi idual
ho mones o pos -menopausal women showed ha p oges e one alone inc eased he basal
a e o muscle p o ein syn hesis bu HT wi h es ogen alone had no signi ican e ec [28].
Hansen and co-wo ke s epo ed ha myo ib illa a es o p o ein syn hesis we e lowe in
pos -menopausal women on es ogen-only HT compa ed o pos -menopausal women no on
any HT [29]. In a sepa a e s udy, hose in es iga o s epo ed ha p emenopausal women
aking o al con acep i e con aining e hinyl es adiol also had a lowe a e o myo ib illa
p o ein syn hesis compa ed o young women no aking o al con acep i es [30].
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Ano he app oach o assess es ogenic impac on a es o muscle p o ein syn hesis is
o compa e a es be ween p e- and pos -menopausal women. Two s udies by Smi h and
cowo ke s showed ha basal a es o muscle p o ein syn hesis we e 20-30% g ea e in pos -
menopausal compa ed o young, p e-menopausal women [28, 31], indica ing ha es ogen
de iciency may imp o e he a e o p o ein syn hesis. O e all, he collec i e e idence poin s
in he di ec ion o es ogens supp essing he a e o muscle p o ein syn hesis in women,
which is coun e in ui i e o he concep ha es ogens will blun he loss o skele al muscle
mass wi h age.
S udies using a ious animal models do no cla i y he impac o es ogen on muscle
p o ein syn hesis. Skele al muscle o o a iec omized a s induced o g ow by eloading he
hindlimbs a e unloading had low le els o p70s6k and Ak compa ed o sham-ope a ed a s
indica ing ha es ogen de iciency impai ed p o ein syn hesis [32]. On he con a y, emale
lambs ea ed wi h a syn he ic es ogen had dec eased a es o muscle p o ein syn hesis,
despi e he ea men causing inc eased g ow h [33]. To h and cowo ke s u ilized a a
o a iec omy model wi h ho mone ea men s and measu ed muscle p o ein syn hesis a es
[34]. O a iec omized a s ha ecei ed a placebo ea men had a es o p o ein syn hesis ha
app oxima ely doubled ha in sham-ope a ed, con ol a s as well as in o a iec omized a s
ha ecei ed es adiol o p oges e one. These esul s pa allel he o e all human esul s o
es ogen de iciency wi h muscle p o ein u no e appea ing o ip owa d anabolism a he
han ca abolism, as a es o p o ein syn hesis end o be g ea e in he absence o es ogen.
Muscle p o ein deg ada ion. Smi h and cowo ke s deduced ha because skele al
muscle o pos -menopausal women is in an o e all ca abolic condi ion, he ela i ely high
a e o p o ein syn hesis in he basal, es ing s a e mus be o se by an e en g ea e a e o
p o ein deg ada ion esul ing in a ne p o ein and muscle loss [31]. Howe e , whole body
p o ein b eakdown did no di e be ween aged, pos -menopausal women no on HT
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compa ed o young women wi h no mal ci cula ing es ogen [35], and myo ib illa p o ein
b eakdown a es did no di e be ween p emenopausal women who did and did no ake
es adiol-based HT [30]. Thus, esul s a e insu icien o suppo he deduc ion ha basal a es
o muscle p o ein deg ada ion a e ele a ed wi h es ogen de iciency.
In animal s udies, skele al muscle p o ein deg ada ion was no a ec ed by es adiol
ea men in g owing s ee s [36]. Though, using bo ine sa elli e cell cul u es, Kamanga-Sollo
and cowo ke s showed ha es adiol ea men dec eased he a e o p o ein deg ada ion and
inc eased he a e o p o ein syn hesis lending suppo o he concep o es ogen being
anabolic [37, 38].
Tu no e summa y. Collec i ely, e idence ha es ogen de iciency causes
dys egula ion in muscle p o ein u no e wi h he balance ipping away om p o ein
syn hesis and owa d p o ein deg ada ion and hus con ibu ing o he loss o muscle mass is
weak. Fu he esea ch, pa icula ly on he p o ein deg ada ion side o p o ein u no e , is
wa an ed. I is wo h no ing, ha he e idence o es ogenic e ec s on p o ein syn hesis and
deg ada ion p esen ed abo e ocus on es ing basal a es. The e is some e idence o educed
esponsi eness o muscle p o ein syn hesis o anabolic s imuli when es ogen is low [26].
Muscle p o ein ubiqui ina ion and p o easome ac i i y. The ubiqui in-p o easome
sys em con ains in acellula machine y o deg ading and u ning o e p o eins, wi h
ubiqui ina ion ha ing unc ions in addi ion o o ches a ing p o eolysis [39]. P o ein
ubiqui ina ion in ol es h ee classes o enzymes ac ing syne gis ically; ubiqui in ac i a ing
enzymes, ubiqui in conjuga ing enzymes and ubiqui in ligases. In addi ion, deubiqui ina ing
enzymes, he ubiqui in-speci ic pep idases (USPs), a e needed o ecycling ubiqui in and o
escuing a p o ein om deg ada ion. The ubiqui in-p o easome sys em is an impo an
media o o skele al muscle p o ein homeos asis and egula ion o muscle mass h ough
c oss alk wi h anabolic and ca abolic signaling pa hways ( e iewed by [40]). The e has been
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li le esea ch o de e mine es ogenic impac on he unc ion o he o e all ubiqui in-
p o easome sys em; wha has been in es iga ed has been di ec ed mos ly a ubiqui in ligases
and pep idases.
The mos p ominen ubiqui in ligases in skele al muscle a e a ogin-1 (o icial name
Fbxo32, also known as MAFbx) and MuRF1 (o icial name TRIM63, also known as MuRF2,
IRF, RNF28), which we e named as a ophy genes because hei high exp ession leads o he
loss o skele al muscle mass whe eas low exp ession gene ally leads o esis ance agains loss
o muscle [41, 42]. The biology o ubiqui in ligases in skele al muscle is complex as ac o s
such as di e ences in muscle ibe ypes, acu e e sus g adual condi ions inducing a ophy,
and sex di e ences obscu e he in luence o hese a ophy genes. Fo ins ance, an
up egula ion o a ogin-1 and MuRF1 genes was epo ed in a ophic muscles o aged male
a s [43], while down egula ion o a ogin-1 and MuRF1 was epo ed in muscles o aged
emale a s [44]. Such esul s o sex di e ences hin a a possible es ogenic e ec , hough
he aged emale a s we e likely o a ian senescen and hus es ogen de icien . Roge s and
co-wo ke s mo e di ec ly in es iga ed es ogenic e ec s on ubiqui in ligases by compa ing
skele al muscle om sham-ope a ed and o a iec omized mice [45]. Muscle om
o a iec omized mice had app oxima ely 2- old lowe exp ession o a ogin-1 and MuRF1
compa ed o sham con ols indica ing ha ubiqui in ligase-induced a ophy was supp essed
when es ogen was lacking.
S ensson and cowo ke s pe o med a mic oa ay s udy o in es iga e he e ec s o
dihyd o es os e one, a non-a oma izable es os e one, and 17β-es adiol on muscle gene
exp ession in gonadec omized male mice [46]. As expec ed, gonadec omy esul ed in educed
muscle mass ha was pa ially e e sed by es adiol and comple ely e e sed by
dihyd o es os e one ea men . Dihyd o es os e one and es adiol egula ed mainly a di e en
se o genes wi h only 13 genes egula ed by bo h sex ho mones. Among hose dually
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in ibe exci a ion o exci a ion-con ac ion coupling o heal hy muscle; a he he majo i y o
in es iga ions ha e ocused on how es ogen a ec s sa come ic p o eins. Skele al muscle
incu s epe i i e inju y h oughou li e, equi ing egene a ion o he con ac ile machine y o
egain s eng h. He e we will also e iew li e a u e suppo ing he con en ion ha
egene a ion o muscle is impai ed when es ogen is lacking in emales. The collec i e
e idence p esen ed indica es ha dynapenia, due o aging o inju y, is exace ba ed by
es ogen de iciency.
Myosin hea y chain. Phillips and co-wo ke s i s specula ed ha o a ian ho mones
in luence muscle s eng h by di ec ly a ec ing c ossb idges, i.e., con ac ile p o eins [8].
They showed ha women did no di e om men in speci ic o ce o adduc o pollicis
muscle a young ages bu pas he age o menopause we e weake han men; HT, howe e ,
p ese ed s eng h in pos menopausal women. Wa anape mpool and Reise mo e di ec ly
implica ed con ac ile p o eins when hey epo ed ha pe meabilized ibe s om
o a iec omized a s p oduced less speci ic o ce han did ibe s om o a y-in ac a es [91].
Con ac ion is ini ia ed in pe meabilized ibe s by di ec applica ion o calcium, hus only
p ocesses downs eam o calcium elease om he sa coplasmic e iculum a e engaged. Such
esul s indica e ha o a ian ho mones a ec a p ocess be ween calcium binding o oponin C
and he in e ac ion o myosin hea y chain binding o ac in and gene a ing o ce.
Since ha ime, e idence con inues o suppo he con en ion ha es ogen a ec s
myosin. Placing a spin p obe on he ca aly ic domain o myosin hea y chain in ibe s om
mice wi h and wi hou hei o a ies, and hen measu ing s ong-binding o myosin o ac in
du ing con ac ion by elec on pa amagne ic esonance spec oscopy, di ec ly demons a ed
ha he gene a ion o o ce a he molecula le el was low wi h es ogen de iciency [92]. A
subsequen s udy showed ha es adiol ea men o o a iec omized mice could p e en and
es o e loss o s ong-binding o myosin o ac in and o ce gene a ion [93]. Ac i e s i ness is

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an indi ec es ima e o myosin bound o ac in du ing con ac ion and esul s using his
measu e a e consis en wi h es ogen exe ing a posi i e in luence on myosin hea y chain
unc ion [93, 94]. Speci ic o ce o isola ed mouse muscles in hese s udies we e also g ea e
in es ogen- eple e compa ed o –de icien mice [92-95] and he es ogenic e ec s a e
media ed h ough es ogen ecep o s [96].
A s udy o pe meabilized single muscle ibe s om pos -menopausal wins p o ides
u he con incing e idence ha es ogen a ec s he unc ion o myosin hea y chain. In his
s udy by Qaisa and cowo ke s, speci ic o ce and myosin unc ion, as de e mined by o ce
pe c ossb idge, was g ea e in ibe s om biopsies o sis e s on HT compa ed o sis e s no
on HT [97].
Myosin hea y chain is an ATPase and ecen ly a no el egula ed s a e o his p o ein
cha ac e ized by ex emely slow ATP u no e du ing elaxa ion (i.e., no du ing con ac ion)
was disco e ed and e med he supe - elaxed s a e (SRX) [98]. Age- ela ed changes in
myosin SRX is speci ic o emales [99] and is egula ed a leas in pa by es adiol [100].
Downs eam mechanisms unde lying es ogenic e ec s on myosin unc ion du ing elaxa ion
a e specula ed o be ela ed o phospho yla ion o myosin’s egula o y ligh chain [99, 100].
Fu he s udies a e equi ed o elucida e he ex en o which he s a e o myosin du ing
elaxa ion ansla es o modula ion o o ce gene a ion du ing con ac ion and hus s eng h in
emales.
Myosin egula o y ligh chain. Myosin consis s o wo hea y chains and wo pai s o
ligh chains ha a e s abilized on he hick ilamen by myosin binding p o ein C. The
egula o y ligh chain (RLC) ac s as a le e a m on he -helical neck egion o he myosin
hea y chain, ansmi ing he ee ene gy o ATP hyd olysis down he neck domain o
ampli y mo emen s o myosin and o ce p oduc ion du ing con ac ion [101]. In skele al
muscle, RLC phospho yla ion modula es myosin s uc u e, o ce, and powe ou pu [102,
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103] and can in luence con ac ile s eng h du ing daily asks [104]. Es ogen has been
implica ed in he egula ion o RLC phospho yla ion and con ac ili y o ca diomyocy es
[105]. In skele al muscle, p o eomic s udies showed age-dependen educ ion o RLC
phospho yla ion in human as us la e alis muscle [106] and in a as - wi ch muscle [107].
Muscle biopsies om young and olde men and women also showed ha phospho yla ion o
RLC was educed in ibe s o old, es ogen-de icien women bu no old men, ela i e o
young coun e pa s [108]. Such esul s implica e es ogenic impac on pos - ansla ional
modi ica ion o myosin RLC.
Di ec e idence ha es ogen modula es phospho yla ion o RLC in skele al muscle
comes om he wo k o Lai and cowo ke s [109]. Es adiol ea men inc eased RLC
phospho yla ion in C2C12 cells, as well as in skele al muscles o o a iec omized mice [109,
110]. The es adiol-induced phospho yla ion o RLC in emale mice was ela ed o o ce
gene a ion as measu ed by pos e anic po en ia ion o o ce [109]. Se e al o he skele al
muscle p o eins including myosin binding p o ein C, myosin essen ial ligh chain, oponin I,
i in, and nebulin, a ec con ac ili y and/o myosin s uc u e when phospho yla ed, bu
whe he o no hose p o eins a e modula ed by es ogen awai addi ional s udies.
The collec i e e idence suppo s he iew ha es ogen enhances muscle s eng h by
a ec ing he unc ion o myosin, speci ically myosin h ough phospho yla ion o he RLC.
Fu u e esea ch o iden i y es ogenic e ec s on o he sa come ic p o eins a e wa an ed, as is
de e mina ion o es ogen-sensi i e kinases ha phospho yla e sa come ic p o eins.
Impai ed egene a ion ollowing inju y. The concep ha epea ed skele al muscle
inju y ollowed by inadequa e epai con ibu es o muscle weakness in he aged has been pu
o h [111-113]. Se e al lines o e idence indica e ha es ogen a ec s he eco e y o
muscle ollowing inju y and hus, es ogen de iciency in emales would heo e ically u he
exace ba e muscle weakness.
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The bes indica o o eco e y om inju y is he capaci y o skele al muscle o
p oduce o ce, ha is, egain s eng h [114]. O a ian ho mones ha e been implica ed in he
eco e y o s eng h in emales because young, adul mice ha a e o a iec omized ha e an
incomple e eco e y o s eng h ollowing con ac ion-induced inju y [115] and es adiol
ea men imp o es eco e y o s eng h ollowing a auma ic eeze inju y [116]. Consis en
bu less di ec e idence o a ole o es ogen comes om wo s udies on aged mice by Rade
and Faulkne . Resul s om hose s udies demons a e ha s eng h eco e y a e eccen ic
con ac ions is subs an ially wo se in 25-29 mon h-old emales [117], which a e p esumably
o a ian senescen and hus es ogen de icien , compa ed o aged males [118].
Mechanis ically, i has been hypo hesized ha egula ion o muscle in lamma ion and
sa elli e cell unc ion a e pe u bed by he loss o es ogen and may con ibu e o impai ed
s eng h eco e y. Al hough he e ec s o es ogen on he in lamma o y esponse ollowing
inju y has been epo ed in a ai numbe o s udies on emales, he esul s a e con lic ing.
The e ec s o es ogen on muscle in lamma ion in s udies on women a e inconsis en wi h
e idence ha es ogen dec eases [119], inc eases [120], o does no a ec [121] in lamma ion
ollowing muscle inju y. Using oden models, s udies show ha es ogen ea men
a enua es [122-125], enhances [120, 126-128], o has no e ec [129, 130] on muscle
in lamma ion. A ecen s udy showed ha a mode a e, physiological dose o es adiol gi en
o o a iec omized mice inc eased he in lamma o y esponse ia ec ui men o neu ophils
ollowing muscle inju y and also demons a ed ha eco e y o s eng h was enhanced
compa ed o a placebo ea men [116]. I was u he p oposed ha he se um le el o
es ogen is a c i ical componen ha needs o be conside ed in u u e esea ch because
sup aphysiological le els o es ogen may elici opposi e in lamma o y e ec s han
physiological le els, con ibu ing o inconsis encies in he li e a u e, as se um es adiol le els
a e o en no eliably measu ed in oden s udies.
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The in lamma o y esponse ollowing skele al muscle inju y subsequen ly a ec s he
myogenic esponse du ing egene a ion (Re iewed by [131]). S udies om Tiidus and
colleagues indica e ha exe cise-induced ac i a ion o sa elli e cells is less e ec i e in he
absence o es ogen [132, 133] and his esponse appea s o be media ed by es ogen
ecep o s [130, 134]. Simila ly, cell cul u e s udies ha e shown an es ogen dose-dependen
inc ease in myogenic cell p oli e a ion [135]. While, he da a in humans is spa se, myogenic
egula o y ac o gene exp ession is acu ely inc eased ollowing eccen ic exe cise in pos -
menopausal women on HT compa ed o hose no on HT [47].
Cu en e idence suppo s he p emise ha es ogen a ec s he egene a ion o
skele al muscle by in luencing he in lamma o y and myogenic esponses, al hough he
unde lying mechanisms a e la gely unknown and awai u u e esea ch. S udies wi h mo e
con olled me hods o es ogen ea men and eliable se um measu emen s, obus ma ke s o
in lamma o y and sa elli e cell unc ions, and de ails o how hose p ocesses ul ima ely a ec
eco e y o muscle s eng h a e needed.
Conclusions
The loss o muscle s eng h in emales due o es ogen de iciency esul s om bo h
inadequa e p ese a ion o skele al muscle mass and quali y o he emaining skele al muscle
(Figu e 1). E idence ha es ogen impac s muscle p o ein u no e and he ubiqui in-
p o easome sys em is o e all weak. The e is s onge e idence ha es ogen p o ec s skele al
muscle agains apop osis ia e ec s on HSPs and mi ochond ia. Thus, when es ogen is
de icien i appea s ha apop o ic pa hways con ibu e o he loss o muscle mass. The
leading candida e causing dynapenia due o es ogen de iciency in emales is myosin.
Modi ica ions o myosin hea y chain unc ion h ough phospho yla ion o myosin RLC ha e
been demons a ed in bo h emale oden models and women. Also con ibu ing o he loss o
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muscle s eng h in emales is abe an in lamma o y and sa elli e cell esponses when
es ogen is de icien . Del ing deepe in o he mechanisms unde lying es ogenic e ec s on
skele al muscle apop osis, sa elli e cells, myosin, and o e all signaling pa hways will u he
in o m scien is s and clinicians designing he apeu ic s a egies o comba sa copenia and
dynapenia.

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Figu e Legend
Figu e 1. Es ogens a ec skele al muscle s eng h in emales by p ese ing muscle mass and
quali y o he con ac ile p o eins. Es ogens in luence he binding o myosin hea y chain o
ac in o gene a e o ce h ough phospho yla ion o he egula o y ligh chain. P ocesses ha
a e impac ed by es ogens a ec ing muscle mass may include p o ein u no e , p o eolysis,
and apop osis. O ganelles ha a e sensi i e o es ogens and con ibu e o main enance o
muscle mass and quali y include nuclei and mi ochond ia. In lamma ion and sa elli e cell
unc ion a e also es ogen sensi i e and can play a ole in ul ima ely p ese ing muscle
s eng h. ER = es ogen ecep o ; P = phospho yla ion; RLC = egula o y ligh chain
Acknowledgemen s
This wo k was suppo ed by Na ional Ins i u es o Heal h g an s R01-AG031743 (DAL) and
T32-DK091317 (BCC), and he Academy o Finland (309504; EKL). We hank Geo gios
Ka a igas o c i ical eading o he manusc ip .
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