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F rontiers in Physiology | 1 November 2015 | V olume 6 | Article 25

!"ite" by#

Russell T.

H epple, McGill University,C anada

$eviewe" by#

Espen Spangenburg,

East Carolina University, U SA

 Aaron Paul Russell,

 Aaron Russell, Australia

%&orr es'on"ence#

Cristop H andscin

cristop. andscin!unibas. c

('eci)lty section#

Tis article "as sub#itted to

Striated Muscle Pysiology ,

a section o$ te %ournal &rontiers in Pysiology 

$eceive"# '( August )*(+ 

 Acce'te"# ), -ctober )*(+ 

Publishe"# * /ove#ber )*(+ 

&it)tion#

0upr 1 and Handscin C 2)*(+3

Co#ple4 Coordination o$ C ell 

Plasticity by a PGC 5(α5controlled 

Transcriptional /et"or6 in

S6eletal Muscle. &ront. Pysiol.

78')+.

doi8 (*.''9:$pys.)*(+.**')+ 

*+N+  $!V+ !,'ublishe"# 0- November 2015

"oi#  10.-/f'hys.2015.0025

&om'le &oo r "in)tion of   &ell 

Pl)sticity by ) P&21α2contr olle"3r)nscri'tion)l Networ4 in (4elet)l*uscle

)rb)r) u'r )n" &hristo'h 7)n"schin %

1io;entru#, University o$ 1asel, 1asel, S"it;erland 

(4elet)l muscle cells ehibit )n enormous 'l)stic c)')city in or"er to )")'t to

etern)l stimuli. !ven though our over)ll un"erst)n"ing of the molecul)r 

mech)nisms th)t un"erlie 'henoty'ic ch)nges in s4elet)l muscle cells rem)ins'oor8 sever)l f)ctors involve" in the regul)tion )n" coor"in)tion of relev)nt

tr)nscri'tion)l 'rogr)ms h)ve been i"entifie" in recent ye)rs. For e)m'le8 the

'eroisome 'rolifer)tor)ctiv)te" rece'tor γ co)ctiv)tor1α 9P&1α:  is ) centr)l

regul)tory neus in the )")'t)tion of muscle to en"ur)nce tr)ining. +ntriguingly8

P&1α integr)tes numerous sign)ling ')thw)ys )n" tr)nsl)tes their )ctivity into

v)rious tr)nscri'tion)l 'rogr)ms. 3his selectivity is in ')rt controlle" by "ifferenti)l

e'ression of P&1α v)ri)nts )n" 'osttr)nsl)tion)l mo"ific)tions of the P&1α

'rotein. P&1αcontrolle" )ctiv)tion of tr)nscri'tion)l networ4s subse;uently

en)bles ) s')tiotem'or)l s'ecific)tion )n" hence )llows ) com'le coor"in)tion

of ch)nges in met)bolic )n" contr)ctile 'ro'erties8 'rotein synthesis )n"

"egr)")tion r)tes )n" other fe)tures of tr)ine" muscle. +n this review8 we "iscuss

recent )"v)nces in our un"erst)n"ing of P&1αregul)te" s4elet)l muscle cell

'l)sticity in he)lth )n" "ise)se.

6eywor"s# s4elet)l muscle8 tr)nscri'tion)l regul)tion8 P&1α8 eercise8 met)bolism8 co2r egul)tor 

+N3$<=>&3+<N

Cell plasticity is often controlled by complex transcriptional networks. While traditionally,

much of the research on such networks was focused on transcription factors, the important

role of co-regulators has been increasingly appreciated in recent years !asgupta et al., "#1$%

&ouchiroud et al., "#1$'. Co-regulator proteins ha(e no intrinsic !)*-binding domain and

thus rely on transcription factors to be recruited to regulatory elements. +he ability of co-regulators to bind to (arious partners enables the regulation of broad, complex transcriptional

 programs. +he peroxisome proliferator-acti(ated receptor γ *γ' coacti(ator-1α C-1α'

is a prototypical member of this class of proteins. /nitially disco(ered in a screen comparing

white and brown adipose tissue, expression of C-1α has subse0uently been documented in

all tissues with a high energetic demand, including brain, kidney, skeletal, and cardiac muscle,

li(er, pancreas, or the retina &artne2-edondo et al., "#13'. +he core function of C-

1α centers on the induction of mitochondrial biogenesis and oxidati(e metabolism. C-1α

likewise controls highly tissue-specific  programs, such as hepatic gluconeogenesis or 

mitochondrial uncoupling in brown adipose tissue. 4ince the phenotype of global C-1α

transgenic and

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u'r )n" 7)n"schin 3r)nscri'tion)l networ4 regul)tion by P&1α

knockout mice is complex 5in et al., "##$% 5iang et al.,

"##6', many insights into organ-specific function and r egulation

of C-1α, including those discussed in this re(iew unless

otherwise stated, ha(e mostly been obtained from murine

tissue- specific gain- and loss-of-function models 7andschin

et al.,

"##3'. /n skeletal muscle, specific o(erexpression of C-1α

at physiological le(els is sufficient to induce an endur ance-

trained phenotype 5in et al., "##"' while super-physiologicalo(erexpression promotes fiber damage and impaired muscle

function 5in et al., "##"% &iura et al., "##8'. /n(ersely, a blation

of C-1α gene expression in this tissue promotes se(eral

typical signs of pathological inacti(ity, including a local and

systemic chronic inflammation 7andschin et al., "##9a,b'. *

r eduction in C-1α gene expression in human skeletal

muscle has  been associated with insulin resistance and type "

diabetes, at least in some patient cohorts atti et al.,

"##:'. ;f note, mice with a hetero2ygous deletion of C-1α

in skeletal muscle also exhibit a dysregulation of glucose

homeostasis 7andschin et al.,

"##9b'.

C-1α integrates the acti(ity of the ma<or signaling pathways that are important in a contracting muscle fiber 

and accordingly, C-1α transcript and protein le(els ar e

ele(ated after a training bout =re2-4chindler and 7andschin,

"#1:'. *s conse0uence, C-1α then controls the biological

 program encompassing all plastic changes of the muscle cell

to endurance exercise. >or example, mice with ele(ated muscle

C-1α le(els exhibit a higher number of mitochondria, a

switch toward oxidati(e, slow-twitch muscle fiber types, alter ed

substrate synthesis and metabolism, and a reduction in muscle

 protein breakdown 7andschin, "#1#'. /mportantly, the effects

of C-1α extend beyond muscle cells? ele(ation of C-

1α in muscle leads to higher tissue (asculari2ation *rany

et al., "##@' and a remodeling of the post- and  pr esyna pticside of the neuromuscular <unction 7andschin et al., "##9c%

*rnold et al., "#1$'. >urthermore, C-1α-regulated endocr ine

mediators, members of the so-called myokine protein family,

 promote beige fat cell differentiation and acti(ation in white

adipose tissue or neurogenesis in the hippocampus and ther e by

dramatically extend the reach of muscle C-1α 4chnyder 

and 7andschin, "#13'. 4urprisingly, while o(erexpression of 

C-1α is sufficient to induce an endurance-trained muscle

 phenotype, se(eral aspects of training adaptation seem to be

retained e(en in mice with a global or muscle-specific k nock out

of this coacti(ator, respecti(ely 5eick et al., "##@% owe et al.,

"#1"'. !iscrepancies in such studies howe(er indicate that the

specific animal model, training type, timing, intensity, and other 

aspects of the exercise protocol are important for the assessment

of the re0uirement of C-1α in exercise adaptation eng et

al.,

"#1#'. >urthermore, these studies imply a redundant r egulation

of these e(olutionarily extremely important plastic changes in

skeletal muscle in which C-1α can be partially replaced by

other, so far unknown regulators. +hus, in a  physiological

setting, C-1α controls a highly complex transcriptional

network that re0uires spatial and temporal specification,

coordination of anabolic and catabolic pathways as well as

 precise acti(ation and termination. /n this mini re(iew, we

highlight some of the recent mechanistic findings that

contribute to the ability of 

C-1α to regulate transcription in such a broad and precise

manner .

+N3!$A3+<N <F&<N3$A&3+<N+N=>&!= (+NA?+NPA37,A@( @ P&1α +N (6!?!3 A?*>(&?!

&uscle fiber contraction is linked to acti(ation by the motor 

neuron, mechanical stress, relati(e tissue physoxia, an alter ed

neuroendocrine milieu, changes in metabolic demand and other 

stimuli that engage (arious signaling pathways. *ll of these

signals con(erge on C-1α and promote a tr anscr i ptional

induction of the gene or induce posttranslational modifications

+&' of the protein Figure 1A', including C-1α  pr otein phosphorylation by (arious kinases on different phosphor ylation

sites, acetylation, methylation, sumoylation, ubi0uitination,

and acetylglucosamination Figure 1B% >ernande2-&arcos and

*uwerx, "#11'. +he effects of most of these modifications on

C-1α function are still poorly understood. 4ome of the +&s

can alter the stability of the C-1α protein or modulate the

interaction with transcription factors or other co-regulators. >or 

example, phosphorylation by the p:@ mitogen-acti(ated  pr oteinkinase p:@ &*A' results in a prolongation of the nor mally

(ery short half-life of the C-1α protein of ∼".3 h uigser(er 

et al., "##1', at least in part by pre(enting ubi0uitination of 

C-1α and therefore stabili2ing the protein ;lson et al.,

"##@'. +he *&-dependent protein kinase *&A' likewise

 phosphorylates the C-1α protein in addition to its positi(e

effect on C-1α gene transcription and predominantly triggers

catabolic pathways to rectify a relati(e energy deficit, e.g., in

exercise Bager et al., "##9'. 4uch a temporal specification is

extremely important to a(oid futile cycles of C-1α-contr olled

anabolic and catabolic pathways, e.g., fatty acid -oxidation and

de no(o lipogenesis 4ummermatter et al., "#1#'. &oreo(er,+&s could also determine spatial differentiation of C-1α

function. >or example, the interaction between C-1α and

the *-binding protein *D, also called nuclear r es pir ator y

factor " or )>"' not only re0uires the presence of host

cell factor 7C>' as an additional adaptor protein, but also

specific phosphorylation e(ents both on C-1α as well as

the *DD1 subunit of the *D complex 7andschin et al.,

"##9c'. +hese +&s can be triggered by motor neur on-

e(oked neuregulin stimulation of the muscle fiber and ther e by

control a specific transcriptional acti(ation of  post-syna ptic

neuromuscular <unction genes by C-1α and *D exclusi(ely

in sub-synaptic nuclei 7andschin et al., "##9c'. +hus, in

addition to the modulation of protein stability, +&s might alter the acti(ity and stability of C-1α as well as the ability to

interact with transcription factors and thereby regulate specific

transcriptional programs 7andschin and 4piegelman, "##8'.

>or most modifications of the C-1α protein, a E+& codeF

5onard and ;Gmalley, "##9' that determines transcription factor 

interaction specificity has not been elucidated. *  pr ototy pical

example for a C-1α +& code howe(er is pro(ided by

the 48 kinase 48A'-mediated phosphorylation that selecti(ely

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F+>$! 1 | &om'le )ctiv)tion of the tr)nscri'tion)l co2)ctiv)tor P&1α by "ifferent sign)ling ')thw)ys. 9A: !ercise triggers ) com'le tr)nscr i'tion)l

)ctiv)tion )s well )s v)rious 'osttr)nsl)tion)l mo"ific)tions to control P&1α levels )n" )ctivity. 9:8 Posttr)nsl)tion)l mo"ific)tions of the P&1α 'rotein. AA8 )mino

)ci"s Ac8 )cetyl)tion A4t8 'rotein 4in)se  A*P8 A*P)ctiv)te" 'rotein 4in)se 2A$8 2 )"renergic rece'tor &)*8 &)2+/c)lmo"ulin"e'en"ent 'rotein 4in)se

&nA8 c)lcineurin A &l428 &"c2li4e 4in)se 2 &$!8 cA*P res'onse element bin"ing 'rotein !$$α8 estrogenrel)te" rece'tor α s48 glycogen synth)se 4in)se

bet) 7NFB α8 he')tic nucle)r f)ctor B α *!F2&/2=8 myocyte enh)ncer f)ctors 2&/= *e8 methyl)tion m3<$&18 m)mm)li)n t)rget of r)')mycin com'le 1

<lN)8 <lin4e" N)cetylglucos)min)tion <38 <lin4e" N)cetylglucos)mine tr)nsfer)se ' *AP8 ' mitogen)ctiv)te" 'rotein 4in)se P+8

'hos'hoinositi"e 4in)se PA8 'rotein 4in)se A P8 'hos'horyl)tion PPA$α8 'eroisome 'rolifer)tor)ctiv)te" rece'tor α P$*318 'rotein )r ginine

methyltr)nsfer)se 1 $+P1B08 rece'tor inter)cting 'rotein 1B0 $NFB8 ring finger 'rotein B (68 (64in)se (&F& "bCH C dc B 8 (&F ubi;uitin lig)se com'le subunit

FwbC/&"cB (+$318 sirtuin1 (u8 sumoyl)tion (umo18 sm)ll ubi;uitin rel)te" mo"ifier 1 >bi8 ubi;uitin)tion @@18 yin y)ng 1.

retains the ability of C-1α to boost fatty acid oxidation

and mitochondrial function while attenuating its effect on

gluconeogenesis in the li(er 5ustig et al., "#11'. &echanistically,

these +&s reduce the interaction between C-1α and the

hepatic nuclear factor $ α 7)>$α', but not co-acti(ation of the

estrogen-related receptor α Iα' or *α. /n addition to

 binding to transcription factors, +&s of the C-1α protein

can

also affect the interaction with other co-regulators. >or example,

the co-repressors p18# myb binding protein p18#&D' and

receptor interacting protein 1$# /1$#' are recruited to C-

1α in a +&-dependent manner ? p18#&D inhibits the ability

of C-1α to regulate mitochondrial gene expression in the

absence of p:@ &*A-mediated phosphorylation >an et al.,

"##$' while /1$# associates with and represses sumoylated

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C-1α ytinki and al(imo, "##6'. ;ther co-repressors r educe

C-1α acti(ity by competing for binding to tr anscr i ption

factors, for example modulation of Iα co-acti(ation by the

nuclear receptor co-repressor 1 )Co1% =re2-4chindler et al.,

"#1"' or of the glucocorticoid receptor by the small

heter odimer  partner 47% Dorgius et al., "##"'. +&-

dependent  binding e(ents are also obser(ed for co-acti(ators as

exemplified by the interaction of C-1α with the &ediator 

1 &I!1' su bunit of the +*H!/Hmediator complex thatis disrupted after phosphorylation of C-1α by the Cdc"-

like kinase " Clk"% +abata et al., "#1$'. Jbi0uitination and

subse0uent pr oteasomal degradation of the C-1α protein form

a negati(e feedback loo p to ensure timely termination of the

C-1α response 4ano et al.,

"##9'. +his process might be triggered by C-1α protein self-

aggregation upon reaching a critical threshold 4ano et al.,

"##9'. +hus, C-1α ser(es as recipient of a multitude of +&s,

ther e by integrates the acti(ity of the respecti(e signaling

 pathways and subse0uently triggers a transcriptional response

that is ada pted to the specific cellular context.

$!>?A3<$@ AN= F>N&3+<NA?=+V!$(+3@ A(!= <N 37! P&1α !N!(3$>&3>$! AN= 3$AN(&$+P3 VA$+AN3(

C-1α gene expression is rapidly and robustly increased in

response to external stimuli that increase the energy demand

such as cold in brown fat, fasting in the li(er, or contraction in

skeletal muscle 5in et al., "##3'. +he c*& response element

 binding protein CID' and the acti(ating transcription f actor -

" *+>-"', both of which bind to c*& response elements

CI', are common regulators of C-1α transcription in most

tissues. /n addition, tissue-specific transcription factors pr o(ide

an additional layer of control, e.g., myocyte enhancer factors

"CH! &I>"C and -"!' in muscle cells =re2-4chindler and

7andschin, "#1:'. * positi(e autoregulatory loop of &I>"CH!

co-acti(ation by C-1α on its own promoter f ur ther mor e

contributes to ade0uate and controlled induction of C-1α

transcription in this tissue 7andschin et al., "##:'. /ntriguingly,

this theme of using cross- and autoregulatory loops, thus

f or ming  biological switches, is also obser(ed in early

downstream tar get gene regulation, for example in the

induction of Iα and *D*  by C-1α &ootha et al.,

"##$'.

C-1α transcription can be initiated from three start sites on

two alternati(e promoters. &oreo(er, alternati(e )*

 processing further increases the number of C-1α transcripts

and, as a conse0uence, protein (ariants &artne2-edondo et

al., "#13'. I(en though the regulatory elements of the two

 pr omoter s ha(e not yet been studied in detail, the proximal

 pr omoter seems to pro(ide a more robust basal expression

while the distal promoter that is approximately 1: kb

upstream exhibits a higher dynamic range in gene expression,

at least in skeletal muscle &artne2-edondo et al., "#13'. /t is

still unclear whether alternati(e promoter usage is closely linked

to the tr anscr i ption of C-1α isoforms. &oreo(er, the

functional conse0uence of the selecti(e expression of most

C-1α transcript (ariants is unknown. 4urprisingly howe(er,

the C-1α$ (ariant seems to

regulate a highly distinct transcriptional program with (ery little

o(erlap compared to that of the other (ariants uas et al.,

"#1"'. C-1α $ contributes to skeletal muscle adaptation to

resistance training and the ensuing fiber hypertrophy uas et al.,

"#1"', at least in certain contexts =re2-4chindler et al., "#1:',

diametrically opposite to the endurance exercise-like phenoty pe

triggered by the other C-1α isoforms. /n humans howe(er,

some studies 0uestioned an exclusi(e correlation between C-

1α$ expression and resistance training 5undberg et al., "#1$'warranting further studies. /n any case howe(er, the gene

structure and transcript processing of C-1α thus  pr o(ide

an additional layer of regulatory and functional specification

7andschin and 4piegelman, "##8'.

P&21α2&<N3$<??!=

3$AN(&$+P3+<NA? N!3,<$6$!>?A3+<N A??<,(&<N3!D3=!P!N=!N3 &<N3$<? AN=

(P!&+F+&A3+<N

;riginally, C-1α has been disco(ered as a coacti(ator of *γ and was hence named accordingly uigser(er et al.,

166@'. /t howe(er became clear that C-1α not only inter acts

with this, but also a number of other nuclear receptors and

non-nuclear receptor transcription factors. /ntriguingly, these

interactions are mediated by different structural domains within

the C-1α protein, with a more )-terminal preference for 

nuclear receptor co-acti(ation while others, for example &I>"

or forkhead box protein 1 >oxo1' bind C-1α closer to

the C-terminus 5in et al., "##3'. +herefore, the f unctional

specificity of C-1α isoforms that lack certain domains of 

the full-length protein could stem from the specific a blation

and enhancement of binding to transcription factor  par tner s

7andschin and 4piegelman, "##8% &artne2-edondo et al.,"#13'. !espite the identification of (arious interaction  partner s,

C-1α seems to ha(e a special relationship with Iα, at least

in the regulation of mitochondrial genes &ootha et al., "##$'.

Iα is an orphan nuclear receptor that is mainly acti(ated

 by co-acti(ator binding in a ligand-independent manner Aallen

et al., "##$'. &oreo(er, C-1α rapidly induces the

tr anscr i ption of Iα as an early response target gene &ootha

et al., "##$'. /t thus is not surprising that pharmacological

inhibition of the interaction between C-1α and Iα or 

knockdown of Iα has a potent effect on many C-1α

target genes in muscle cells &ootha et al., "##$% 4chreiber 

et al., "##$'. * global analysis of C-1α recruitment to

regulatory elements in the mouse genome combined with anexpression analysis howe(er re(ealed a so-far largely

underestimated number of  putati(e transcription factor 

 partners beyond Iα to be in(ol(ed in C-1α-mediated

target gene regulation in muscle cells Daresic et al., "#1$'.

>urthermore, transcription factor motif acti(ity response

analysis not only predicts Iα to be in(ol(ed in the

regulation of primary, but also secondary C-1α target genes,

thus both in the co-acti(ated state but also working without

C-

1α in this context. +hese data indicate a much higher complexity

of transcription factor engagement by C-1α than pre(iously

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suggested. 4econd, the combination of C-1α Ch/se0 and

gene expression data re(ealed that of the high number of C-1α repressed genes, only a small minority, ∼3K, ha(e a C-

1α !)* recruitment peak within a distance of ±1# kb of their 

 promoter. *ccordingly, the findings imply that the effect of C-

1α on gene repression is  predominantly indirect and that C-

1α lacks an intrinsic inhibitory function Daresic et al., "#1$'.

While a systematic analysis of gene repression by C-1α

r emains to be done, C-1α-dependent reduction of theacti(ating phosphorylation of the p83 subunit of the nuclear 

factor LD )>-LD% Iisele et al., "#1:' could account for at

least some of the indirect inhibitory effect of C-1α on  pr o-

inflammator y muscle gene expression Iisele and 7andschin,

"#1$'. +hird, this systematic study re(ealed no(el insights into

the mechanisms that ensure functional redundancy and

complementation of C-1α- mediated transcriptional control.

rincipal component analysis of the transcription factor 

 binding motifs within the regions of C-1α !)* recruitment

implied an important role for the acti(ator protein-1 *-1'

transcription factor complex in C-

1α-controlled gene expression Daresic et al., "#1$'. *-1 is a

well-studied stress response gene in (arious cellular contexts,

 but has so far ne(er been associated with C-1α f unction

in muscle. /nterestingly, the group of direct targets for *-1

and C-1α was significantly enriched in genes associated with

the cellular response to hypoxia, including se(eral r egulator s

of (asculari2ation. +his regulation complements the pre(iously

disco(ered control of the expression of the (ascular endothelial

growth factor MI>' by C-1α and Iα *rany et al.,

"##@'. +hese findings imply that this seemingly r edundant

usage of different transcription factors to regulate the same

 biological program ensures ade0uate regulation of this critical

 process. *lternati(ely, the ability of C-1α to enhance the

transcriptional acti(ity of different partners might also indicate

that C-1α is able to regulate the respecti(e target genes

in different cellular contexts, e.g., by binding to Iα in a

metabolically stressed muscle cell and acting together with *-1

upon reduced physoxic conditions Figure 2'. Ixercise triggers

a hypoxic response including an acti(ation of the hypoxia-

inducible factor-1 7/>-1' in muscle cells by a lowering of the

relati(e tissue oxygen a(ailability due to a dysbalance between

oxygen consumption and supply, exacerbated by contr action-

mediated constriction of blood (essels 5indholm and und0(ist,

"#13'. +ogether, the current data highlight the (ast complexity

of di(erse mechanisms by which C-1α exerts a  pleiotr opic

response in muscle cells.

&<N&?>(+<N( AN= <>3?<<6

/n essence, C-1α is a protein docking platform that on one

side is recruited to transcription factors bound to their tar get

gene promoters and enhancers, and on the other side inter acts

with components of the histone acetyltransferase uigser(er 

et al., 1666', +*H!/Hmediator Wallberg et al., "##:',

and 4W/H4)> 5i et al., "##@' co-regulator protein complexes.

+hereby, C-1α greatly boosts transcription e(en though

C-1α lacks any discernable intrinsic en2ymatic acti(ity.

!espite this ostensible simplicity in function, C-1α can

F+>$! 2 | P&1α eng)ges "ifferent tr)nscri'tion f)ctors to r obustly

regul)te biologic)l 'rogr)ms. &o)ctiv)tion of the estr ogen2r el)te"

rece'tor α 9!$$α: )n" the )ctiv)tor 'rotein1 tr)nscri'tion f)ctor com'le

9 AP21: )llow ) "ifferenti)l regul)tion of the gene 'rogr)m for v)scul)r iE)tion8

cyto'rotection8 )n" hy'oi) res'onse triggere" by "ifferent stimuli8 e.g.8 )

ch)nge in the met)bolic "em)n" )n" the ensuing )ngiogenesis to im'r ove

substr)te )v)il)bility or neov)scul)riE)tion )s ) res'onse to )

contr)ctionme"i)te" re"uction in tissue 'hysoi) )n" )n ensuing

reoygen)tion for )"e;u)te oygen su''ly. (PP18 secrete" 'hos'ho'r otein

1 V!F8 v)scul)r en"otheli)l growth f)ctor.

control highly complex transcriptional programs in (arious

tissues with a significant impact on organ plasticity. +he

ability of C-1α to integrate different signaling pathways

through a multitude of +&s, selecti(e acti(ation of alternati(e

 promoters and expression of transcript (ariants could  pr o(ide

a mechanistic explanation for the key regulatory function of 

C-1α in the regulation of tissue phenotypes. 7owe(er, mor e

studies will be re0uired to obtain a better understanding and

o(er(iew on the different aspects of the regulation of a co-

acti(ator-controlled transcriptional network, which not only isof high interest to understand the basic biology, but could

also ha(e a significant clinical impact. /n a physiological and

 pathophysiological context, ele(ation of C-1α in muscle

 promotes a high endurance phenotype and ameliorates (arious

muscle diseases with different etiologies, including !uchenne

muscular dystrophy 7andschin et al., "##9c', dener (ation-

induced fiber atrophy 4andri et al., "##8', or sarcopenia Wen2

et al., "#1$', respecti(ely. +o date, it is not clear which f unctions

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of muscle C-1α are responsible for such a broad ther a peutic

effect 7andschin, "##6'. 4imilarly, pharmacological agents that

robustly, specifically and safely ele(ate C-1α in skeletal muscle

in the desired therapeutic window remain elusi(e 4(ensson

and 7andschin, "#1$'. >inally, based on studies with muscle-

specific C-1α transgenic animals that ha(e an accelerated

de(elopment of insulin resistance on a high fat diet Choi

et al., "##@', which can only be rectified by bona fide physical

acti(ity 4ummermatter et al., "#1:', the application of so-called Eexercise mimetics,F compounds that elicit exercise-

like effects in muscle and other tissues, might be

 pr oblematic. +herefore, to design partial exercise mimetics or 

new com pounds that specifically acti(ate certain functions of 

C-1α,  better knowledge about upstream regulators and

downstream effects on the transcriptional network are needed.

/n particular, e(en though a strong correlation between muscle

C-1α expression, exercise, and diseases states has been

repeatedly documented in

humans e.g., see 4il(ennoinen et al., "#13', information a bout

the regulation and function of human muscle C-1α so far 

remains largely descripti(e. Jntil further insights are obtained,

 physical acti(ity thus remains a cheap and effecti(e way for the

 pre(ention and treatment of many chronic diseases 7andschin

and 4piegelman, "##@', at least in exercise-tolerant patients.

 A&6N<,?!=*!N3(

We thank 4(enia 4chnyder for critical comments on the

manuscript. Work in our lab is supported by the IC

Consolidator grant 818@:#-&J4C5IN)I+, the 4wiss )ational

4cience >oundation, 4ystemsO.ch, the 4wiss 4ociety for esearch

on &uscle !iseases 44I&', the E)o(artis 4tiftung f Pr 

medi2inisch-biologische >orschung,F the Jni(ersity of Dasel

and the Dio2entrum. DA is supported by the Dio2entrum

Dasel /nternational h! rogram E>ellowships for Ixcellence.F

$!F!$!N&!(

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Conflict of Interest Statement: +he authors declare that the research was

conducted in the absence of any commercial or financial relationships that could

 be construed as a potential conflict of interest.

Copyright V "#13 Aupr and 7andschin. +his is an open-access article distributed

under the terms of the Cr e a ti(e Commons *tt r ibu tion 5 icense C C DR'. +he use,

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