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Exe cise Medicine o Cance Cachexia : Ta ge ed Exe cise o Coun e ac Mechanisms
and T ea men Side E ec s
© The Au ho (s) 2022
Published e sion
Ma opalias, Geo gios; Sim, Ma c; Taa e, Dennis, R.; Gal ão, Daniel A.; Sp y,
Nigel; K aeme , William, J.; Häkkinen, Keijo; New on, Robe , U.
Ma opalias, G., Sim, M., Taa e, D., Gal ão, D. A., Sp y, N., K aeme , W., Häkkinen, K., &
New on, R. (2022). Exe cise Medicine o Cance Cachexia : Ta ge ed Exe cise o Coun e ac
Mechanisms and T ea men Side E ec s. Jou nal o Cance Resea ch and Clinical Oncology,
148(6), 1389-1406. h ps://doi.o g/10.1007/s00432-022-03927-0
2022
Vol.:(0123456789)
1 3
Jou nal o Cance Resea ch and Clinical Oncology
h ps://doi.o g/10.1007/s00432-022-03927-0
REVIEW – CLINICAL ONCOLOGY
Exe cise medicine o cance cachexia: a ge ed exe cise ocoun e ac
mechanisms and ea men side e ec s
Geo giosMa opalias1,2 · Ma cSim2,3,4· DennisR.Taa e1,2· DanielA.Gal ão1,2· NigelSp y1,2·
WilliamJ.K aeme 1,2,5· KeijoHäkkinen6· Robe U.New on1,2
Recei ed: 6 Decembe 2021 / Accep ed: 13 Janua y 2022
© The Au ho (s) 2022
Abs ac
Pu pose Cance -induced muscle was ing (i.e., cance cachexia, CC) is a common and de as a ing synd ome ha esul s in
he dea h o mo e han 1 in 5 pa ien s. Al hough p ima ily a esul o ele a ed in lamma ion, he e a e mul iple mechanisms
ha complemen and ampli y one ano he . Resea ch on he use o exe cise o manage CC is s ill limi ed, while exe cise o CC
managemen has been ecen ly discou aged. Mo eo e , he e is a lack o unde s anding ha exe cise is no a single medicine,
bu mode, ype, dosage, and iming (exe cise p esc ip ion) ha e dis inc heal h ou comes. The pu pose o his e iew was o
examine he e ec s o hese modes and sub ypes o iden i y he mos op imal o m and dosage o exe cise he apy speci ic
o each unde lying mechanism o CC.
Me hods The ele an li e a u es om MEDLINE and Scopus da abases we e examined.
Resul s Exe cise can coun e ac he mos p ominen mechanisms and signs o CC including muscle was ing, inc eased p o-
ein u no e , sys emic in lamma ion, educed appe i e and ano exia, inc eased ene gy expendi u e and a was ing, insulin
esis ance, me abolic dys egula ion, gu dysbiosis, hypogonadism, impai ed oxida i e capaci y, mi ochond ial dys unc ion,
and cance ea men s side-e ec s. The e a e di e en modes o exe cise, and each mode has di e en sub- ypes ha induce
as ly di e se changes when pe o med o e mul iple sessions. Choosing subop imal exe cise modes, ypes, o dosages can
be coun e p oduc i e and could u he con ibu e o he mechanisms o CC wi hou impac ing muscle g ow h.
Conclusion A ailable e idence shows ha pa ien s wi h CC can sa ely unde ake highe -in ensi y esis ance exe cise p o-
g ams, and bene i om inc eases in body mass and muscle mass.
Keywo ds Cance cachexia· In lamma ion· Tumo · Exe cise· Muscle was ing· Muscle a ophy
Abb e ia ions
CC Cance cachexia
CRP C- eac i e p o ein
HIIET Highe -in ensi y in e al endu ance aining
HOMA Homeos asis model assessmen
IGF-1 Insulin-like g ow h ac o 1
LICET Low-in ensi y con inuous endu ance aining
mTORC1 MTOR complex 1
RET Resis ance exe cise aining
TNF-α Tumo -nec osis ac o alpha
In oduc ion
Among he mos de imen al side e ec s o cance and ea -
men is cachexia, a mul i ac o ial me abolic and immune
sys em imbalance (Tisdale 2005). Cance cachexia (CC) is
he ongoing skele al muscle loss (wi h o wi hou a mass
* Geo gios Ma opalias
geo gios.ma[email p o ec ed]
1 Exe cise Medicine Resea ch Ins i u e, Edi h Cowan
Uni e si y, 270 Joondalup D i e, Joondalup, WA6027,
Aus alia
2 School o Medical andHeal h Sciences, Edi h Cowan
Uni e si y, Joondalup, Aus alia
3 Ins i u e o Nu i ion Resea ch, Edi h Cowan Uni e si y,
Joondalup, Aus alia
4 Medical School, Uni e si y o Wes e n Aus alia, Pe h,
Aus alia
5 Depa men o Human Sciences, Ohio S a e Uni e si y,
Columbus, USA
6 Neu omuscula Resea ch Cen e , Facul y o Spo andHeal h
Sciences, Uni e si y o Jy äskylä, Jy askyla, Finland
Jou nal o Cance Resea ch and Clinical Oncology
1 3
loss) du ing cance mani es a ion and ea men , which can-
no be e e sed by con en ional nu i ional suppo , leading
o p og essi e unc ional impai men and dea h (Fea on e al.
2011). Hal o all cance pa ien s de elop cachexia, and his
es ima e inc eases o 80% in hospi alized o ad anced-s age
pa ien s (Tisdale 2003). Cachexia is obse ed in 80% o gas-
ic, panc ea ic, and esophageal, ~ 70% o head-and-neck,
~ 60% o lung, colo ec al, lymphoma, and p os a e, and 54%
o malignan pleu al meso helioma cance pa ien s (La iano
and Meguid 1996). Mo eo e , CC is he immedia e cause
o dea h o a leas 22% o all cance pa ien s (A gilés e al.
2014). No ably, aside om cance , cachexia is obse ed in
he la e s ages o almos e e y majo ch onic illness (Fa kas
e al. 2013), such as HIV/AIDS (p e alence 35%), ch onic
hea ailu e and ch onic obs uc i e pulmona y disease
(20%), ch onic kidney disease (40%), and heuma oid a h i-
is (10%) ( on Haehling and Anke 2010). Despi e he p e a-
lence and se e i y, cachexia emains unde - esea ched, while
ea men op ions a e limi ed, due o ea men inadequacy
and inconsis ency (Roeland e al. 2020).
CC p og ession is o en desc ibed as a con inuum,
ad ancing om p e-cachexia o cachexia, and inally o
e ac o y cachexia, whe e he expec ed su i al is less
han 3mon hs (Fea on e al. 2011). E en hough i s pa ho-
logic mechanisms a e complex (see Fig.1), i is o en mis-
akenly ega ded as a uni o m condi ion, wi h li le unde -
s anding ha he unde lying causes can be he e ogeneous.
Causes o CC can be malnu i ion/ano exia (F ed ix e al.
1990), ele a ed in lamma ion (Tisdale 2005; A gilés e al.
2014), o e en ea men s such as chemo he apy (B ie ley
e al. 2019). Due o he complexi y and a ying p opo ion
o unde lying causes, a one-size- i s-all app oach canno
be assumed, and di e en ea men s a egies mus be
employed o coun e ac he pa ien ’s mechanism p o ile.
While pha macological in e en ions o educe in lam-
ma ion, s imula e appe i e, o educe muscle was ing
al eady exis (Sae eaw e al. 2020), hese should ideally
be accompanied wi h adjunc non-pha macological ea -
men s, such as exe cise, o ampli y ea men e ec i eness.
Awa eness ha exe cise as a medicine can be e ec i e
and eliable in cance suppo i e ca e is well-es ablished
(Schmi z e al. 2019); howe e , he e is a lack o unde -
s anding ha exe cise is no a single medicine, bu mode,
ype, dosage, and iming (exe cise p esc ip ion) ha e dis-
inc e ec s on he componen s o heal h and i ness. Fo
example, esis ance exe cise aining (RET) consis s o
high- ension muscle con ac ions agains a hea y ex e nal
load and when pe o med egula ly and in su icien ol-
ume leads o inc eased muscle mass and s eng h (G gic
e al. 2019). On he o he hand, endu ance exe cise con-
sis s o long du a ions o low- ension muscle con ac ions
which esul in inc eased espi a ion, ca diac ou pu ,
and blood low, leading o inc eased oxida i e capaci y,
imp o ed ca dio ascula unc ion, and a igue esis ance
(Egan and Zie a h 2013). The e o e, he di e en exe cise
modes will be e iewed o explo e po en ial applica ions
o a ge ed exe cise medicine o CC managemen .
Apa om di e en exe cise modes, di e en ypes o each
mode can also elici dis inc and clinically- ele an ou comes.
Fo example, du ing RET, di e en con ac ions a e pe -
o med, such as concen ic, eccen ic, and isome ic. Eccen ic
(leng hening) con ac ions a e pe o med when he o ce gen-
e a ed by he muscle is less han he ex e nal load, causing he
muscle o leng hen while esis ing he ex e nal load. In con-
as , concen ic (sho ening) con ac ions in which he o ce
is g ea e han he load, allows he muscle o sho en (Vog
and Hoppele 2014). Du ing exe cise composed o eccen ic
con ac ions (eccen ic RET), he same muscle wo k can be
p oduced wi h only ~ 15% o he me abolic demand o equi a-
len concen ic RET, which enables he pe o mance o mo e
con ac ions o he same e o (Las ayo e al. 1999). Simi-
la ly in endu ance aining, due o cance - ela ed a igue and
educed physical capaci y, non-con inuous aining (in e al)
wi h sho bu s s o wo k and longe es s migh be mo e ole -
able han a single con inuous e o . Mo eo e , highe -in ensi y
in e al endu ance aining (HIIET) is as e ec i e a inc easing
muscle oxida i e capaci y as lowe -in ensi y con inuous endu -
ance aining (LICET) (Gibala and McGee 2008).
Recen ly, he Ame ican Socie y o Clinical Oncology
published hei guideline on he managemen o CC and
concluded ha exe cise a e he onse o CC is ine ec i e
(Roeland e al. 2020), and he e o e no ecommended. These
ecommenda ions a e pa icula ly su p ising, gi en ha hey
we e based on no ials (Roeland e al. 2020). E en in animal
CC models, RET inc eases body (Dona o e al. 2013) and
muscle mass (Ha dee e al. 2016). Mo eo e , RET ials in
cance pa ien s wi h pa icula ly agg essi e CC o ms (e.g.,
panc ea ic cance ) al eady exis (Table1). No ably, RET did
no only p ese e muscle mass in pa ien s wi h panc ea ic
and lung CC (Nai o e al. 2019), bu e en inc eased body
(Wiskemann e al. 2019) and muscle mass (Kamel e al. 2020)
in pa ien s wi h panc ea ic CC, and inc eased muscle mass in
head and neck cance pa ien s unde going adio he apy wi h
la ge (> 8.5%) body mass loss (Lønb o e al. 2013a). The e-
o e, CC pa ien s may expe ience clinically-signi ican muscle
mass and s eng h gains ollowing supe ised RET (Lønb o
e al. 2013a; Nai o e al. 2019; Wiskemann e al. 2019; Kamel
e al. 2020). Howe e , mo e ials a e needed o examine he
mos e ec i e RET ype, and he speci ic exe cise pa ame e s
(i.e., in ensi y, olume, ime unde ension) o simul aneously
inc ease muscle mass and educe in lamma ion.
The pu pose o his e iew is o examine he mos p omi-
nen CC mechanisms, and p o ide a a ionale o esea ch
ecommenda ions on speci ic exe cise modes (and ypes) ha
could be used as a a ge ed non-pha macological he apy in e-
g a ed wi h he pa ien ’s clinical ea men plan o no only
Jou nal o Cance Resea ch and Clinical Oncology
1 3
educe he side e ec s o cance ea men s bu also imp o e
hei e ec i eness, and educe disease se e i y by e e sing he
mul iple physiological mechanisms d i ing CC.
Muscle mass was ing andinc eased p o ein
u no e
The mos de as a ing symp om o CC is muscle was ing,
which can esul om a a ie y o mechanisms (Fig.1).
Muscle mass is sus ained by an in ica e balance o p o ein
b eakdown and syn hesis, known as p o ein u no e . Mus-
cle p o eins a e in a cons an s a e o u no e o main ain
p o ein homeos asis, bu CC dis up s his p ocess, as he e is
simul aneously excessi e p o ein b eakdown and supp essed
p o ein syn hesis (Whi e e al. 2013). Al hough inc eased
body mass is desi able du ing CC, i is mo e impo an o
he gained mass o be composed o muscle a he han a .
Speci ically, skele al muscle is an impo an esou ce o
Fig. 1 Cachexia mechanisms. APR acu e phase esponse, CRP
C- eac i e p o ein, ECM ex acellula ma ix, IGF-1 insulin g ow h
ac o 1, IL in e leukin (1–11), INF-γ in e e on gamma, LMF lipid-
mobilizing ac o , PIF p o eolysis-inducing ac o , REE es ing
ene gy expendi u e, TGF-β ans o ming g ow h ac o be a, TNF-α
umo nec osis ac o alpha
Jou nal o Cance Resea ch and Clinical Oncology
1 3
Table 1 Exe cise aining ials in ol ing humans wi h cance cachexia
S udy Popula ion Cachexia c i e ia In e en ion Ou comes
Bland e al. (2021) 162 cance pa ien s 6-mon h BM loss a baseline was
10.4%; 7 (4%) pa ien s had p e-
cachexia, 83 (51%) had cachexia,
and 29 (18%) had e ac o y
cachexia
Mul idisciplina y clinical se ice o
cance cachexia; same as Vaughan
e al. (2020)
S abilized BM be ween 6-week isi s
o he clinic, imp o ed physical unc-
ion, pain, nausea, appe i e, ano exia-
cachexia symp oms, physical,
emo ional and unc ional wellbeing
Capozzi e al. (2016) 60 head and neck cance pa ien s
unde going adio he apy
12-week li es yle in e en ion and
p og essi e RET
The p og am ailed o educe loss o
lean BM (−5kg) bu imp o ed qual-
i y o li e, dep ession, and nu i ional
sco es
Del Fabb o e al. (2011) 151 pa ien s wi h cance cachexia His o y o BM loss ≥ 5% (median
was 9%)
Die a y counseling by a die ician and
s anda d exe cise ecommenda ions
in an exe cise clinic
Inc eased appe i e and BM o hose
who e u ned o a second isi
Denehy e al. (2020) 45 pa ien s wi h inope able lung
cance
41% had CC 6-week biweekly home-based LICET Be e physical s eng h in adhe en
han non-adhe en g oup, wi hou di -
e ences in quali y o li e and disease
symp oms
G o e e al. (2018) 12 head and neck cance pa ien s
unde going adio he apy
BM loss (7.1%) A leas 13 sessions o RET (3 se s;
8–12 RM)
Inc eases in muscle s eng h bu di e -
ence be ween g oups in lean BM was
no signi ican (in e en ion: + 1%,
usual-ca e: −3%)
Kamel e al. (2020) Pa ien s wi h panc ea ic CC BM loss > 5% o e he pas 6mon hs 12-week (2 week−1) whole-body RET
(50–80% o he pa icipan ’s 1-RM;
3 se s; 8–12 epe i ions)
Imp o emen s in mobili y, muscle
mass, and s eng h, o bo h uppe -
and lowe -limbs o e a non-exe cis-
ing g oup
Lønb o e al. (2013b) 21 head and neck cance pa ien s
unde going adio he apy
La ge BM loss > 8.5% in 2mon hs 12-week (30 sessions) whole-body
RET wi h o wi hou c ea ine and
p o ein supplemen a ion
5% inc ease in lean BM o he supple-
men a ion and 2.8% o he exe cise-
only g oup. Bo h inc eased s eng h
Lønb o e al. (2013a) 36 head and neck cance pa ien s
unde going adio he apy
La ge BM loss > 8.5% in 2mon hs 12-week (30 sessions) whole-body
RET (2–3 se s o 8–15 RM)
4.3% inc ease in lean BM and
inc eased muscle s eng h
Nai o e al. (2019) Ad anced panc ea ic and lung cance
scheduled o chemo he apy
BM loss o > 5% du ing he p eceding
6mon hs o > 2% in pa ien s wi h a
BM index < 20kg/m2; CC in 40%
o pa ien s
8weeks o nu i ional counseling,
supplemen a ion (b anched-chain
amino acids, coenzyme Q10, and
L-ca ni ine) home-based body-
weigh RET 3 se s o 10 epe i ions
Body and skele al muscle mass, and
muscle unc ion we e main ained
Niels e al. (2018) Case-s udy o s age IV panc ea ic
cance pa ien unde going chemo-
he apy
Typically expec ed 30% BM loss in
pa ien
12-week biweekly RET (8–12 epe i-
ions and 2 se s wi h 70–80% o
ep-max), and LICET (70–80% o
maximum o wa ) 16min, 2 se s
Main ained BM, inc eased s eng h
Roge s e al. (2013) 15 head and neck cance pa ien s
unde going adio he apy
BM loss 12-week RET (exe cise bands);
6-week supe ised; 6-week unsu-
pe ised
Usual-ca e g oup los 5.5kg o lean
BM, while in e en ion g oup los
only 0.4

Jou nal o Cance Resea ch and Clinical Oncology
1 3
BM body mass, CC cance cachexia, LICET low-in ensi y con inuous endu ance aining, RET esis ance exe cise aining, RM epe i ion maximum
Table 1 (con inued)
S udy Popula ion Cachexia c i e ia In e en ion Ou comes
Kaasa e al. (2015), Solheim
e al. (2017), Bals ad e al.
(2020)
Panc ea ic o lung cance commenc-
ing chemo he apy
BM index < 30kg/m2; and < 20% BM
loss in he p e ious 6mon hs
6weeks o (a) an i-in lamma o y
medica ion, (b) EPA supplemen a-
ion, (c) nu i ional counseling, (d)
biweekly home-based LICET and
RET
E en hough only con ol g oup los
BM, bo h los muscle mass
S o ck e al. (2020) 52 ad anced cance pa ien s 12-week leucine- ich supplemen a-
ion, nu i ion, and exe cise p og am
Inc eases in lean BM did no each
signi icance s usual-ca e. Inc eases
in handg ip s eng h, end o
imp o emen in nu i ional s a us,
die a y in ake, a igue, quali y o li e
and clinical cou se
Vaughan e al. (2020) 99 cance pa ien s 6% o pa ien s we e p e-cachec ic
(BM loss < 5%), 64% we e cachec-
ic (BM loss ≥ 5% o BMI < 20 wi h
BM loss > 2%, sys emic in lam-
ma ion), and 30% had e ac o y
cachexia (su i al < 90days, BM
loss ≥ 5% o BMI < 20 wi h weigh
loss > 2%)
6-week home-based RET (5 exe -
cises; ~ 4 week−1), high ene gy and
p o ein die s, supplemen a ion o
ish oil, zinc, and mul i- i amins
49% displayed posi i e ou comes wi h
> 2-kg BM gain be ween wo con-
secu i e appoin men s, 54% inc eased
mid-uppe a m muscle ci cum e -
ence, and > 50% imp o ed unc ional
s eng h be ween wo consecu i e
appoin men s
Wiskemann e al. (2019) 65 pa ien s wi h panc ea ic cance Hal o he pa ien s had BM loss
(≥ 10% in las 6mon hs)
6-mon hs (2 week−1) whole-body
RET ei he a home o pe o med
unde supe ision in an exe cise
clinic (50–80% o 1-RM, 3 se s;
8–12 epe i ions)
Highe adhe ence when home-based
(78.4%) e sus clinic-based (64.1%),
bu only he clinic-based g oup
signi ican ly inc eased uppe - and
lowe -body s eng h, and BM (3.1%)
o e a non-exe cising g oup
Jou nal o Cance Resea ch and Clinical Oncology
1 3
cance pa ien s, no only o me abolic, ho monal, and physi-
cal capaci y easons, bu also because low muscle mass sig-
ni ican ly p edic s chemo he apy-induced oxici y and su -
i al (Pin e al. 2018).
I is well es ablished om a a ie y o s udies ha RET
s imula es myo ib illa p o ein syn hesis, whe eas endu -
ance aining s imula es mi ochond ial syn hesis (G gic e al.
2019). Consequen ly, endu ance exe cise aining does no
p omo e he same deg ee o skele al muscle hype ophy as
RET (G gic e al. 2019). Howe e , ecen e iews on exe -
cise du ing CC ha e su p isingly ecommended endu ance
o e RET o p e en ing muscle was ing du ing CC (Aquila
e al. 2020). In ac , when pe o ming LICET concu en ly
wi h RET, i can esul in smalle muscle g ow h compa ed
o RET alone due o physiological in e e ence (Wilson e al.
2012). Fo example, we ha e epo ed ha p os a e cance
pa ien s who unde wen and ogen-dep i a ion he apy and
RET, had g ea e inc eases in appendicula muscle mass
e sus hose ha included addi ional 20–30min o LICET
(New on e al. 2019). Ne e heless, s udies wi h p eclinical
models showed ha endu ance exe cise migh p e en mus-
cle loss (Jee e al. 2016), howe e , only he mice unde go-
ing highe -in ensi y ac i i y (90% o maximum hea a e,
e e y second day exe cise o 45min) p ese ed hei mus-
cle weigh , while mode a e in ensi ies (70% o maximum
hea a e) did no elici he same e ec s (Jee e al. 2016).
Mo eo e , lack o adequa e in ensi y could ha e led o null
indings in a s udy whe e pa ien s wi h lung and panc ea ic
CC unde going adio he apy unde wen 6-weeks o home-
based exe cise and supplemen a ion (Solheim e al. 2017).
The p og am consis ed o wice-weekly LICET (30min) and
h ice-weekly RET, howe e , he exe cises pe o med we e
o e y ligh loads, such as body-weigh pushups agains
he wall, and ailed o signi ican ly educe muscle was ing
(Solheim e al. 2017). O e all, cu en e idence sugges s
ha hea ie muscle loading is p e e able and likely o be
essen ial o hype ophy.
Du ing CC, me abolic and signaling pa hways ha
inc ease p o ein syn hesis a e supp essed while pa hways
ha dec ease p o ein syn hesis a e ac i a ed, wi h his
phenomenon conside ed he p ima y mechanism o mus-
cle was ing (Tisdale 2009). Speci ically, ype II myo ibe
a ophy is pa icula ly p e alen du ing CC, occu ing o a
g ea e deg ee han ype I myo ibe a ophy (Mendell and
Engel 1971). Mo eo e , i is well-es ablished ha mTOR
complex 1 (mTORC1) plays a cen al ole in mechanical
load-induced muscle g ow h by ac i a ing downs eam
subs a es such as p70S6k, which is an in eg al pa hway
o muscle p o ein syn hesis (Goodman e al. 2011). This
pa hway is egula ed by signaling molecules such as insu-
lin-like g ow h ac o 1 (IGF-1), which is p og essi ely
dec eased in issue and blood du ing CC (Whi e e al. 2013;
Ma ins e al. 2018). Howe e , i appea s ha his p oblem
is mul i- ace ed, as exogenous IGF-1 ea men does no
a enua e CC-induced muscle was ing (Cos elli e al. 2006).
Addi ionally, pa hways ha supp ess p o ein syn hesis, such
as hose in ol ing AMPK, FoxO, STAT3, and myos a in a e
up- egula ed du ing CC (Whi e e al. 2013; Ha dee e al.
2016, 2020). P e ious in es iga ions showed ha eccen ic
RET s imula es pa hways commonly a ec ed du ing CC
ha cause muscle hype ophy (IGF-1, mTORC1, p70S6k)
and supp essed pa hways ha cause a ophy (FoxO, AMPK,
STAT3, MuRF-1, myos a in) (Ha dee e al. 2016, 2020;
Ta ebayashi e al. 2018; Ma ins e al. 2018), and hose
e ec s a e o en g ea e compa ed o equi alen concen ic
RET. Addi ionally, g ea e inc eases in ype II myo ibe
size a e obse ed om eccen ic compa ed o concen ic
o e en con en ional RET (bo h concen ic + eccen ic),
a leas in heal hy humans (Ha he e al. 1991; Ho obágyi
e al. 1996, 2000; F iedmann e al. 2004; F iedmann-Be e
e al. 2010; English e al. 2014; Ho wa h e al. 2019). CC
educes muscle p o ein syn hesis, pa ially h ough ele a ed
IL-6 (Tisdale 2005; A gilés e al. 2014). Ne e heless, 14
sessions o maximal eccen ic RET e ec i ely inc eased
p o ein syn hesis (p70S6K and pS6), e e sed inhibi o s o
p o ein syn hesis (MuRF-1), and educed he CC-induced
a ophy in mouse gas ocnemius (Ta ebayashi e al. 2018).
This was also e i ied by ano he g oup, as eigh sessions
o maximal eccen ic RET imp o ed oxida i e me abolism,
educed muscle was ing, and inc eased basal muscle p o ein
syn hesis and mTORC1, and su p isingly, hese imp o e-
men s we e posi i ely co ela ed wi h plasma IL-6 le els
(Ha dee e al. 2020). These indings ha e signi ican impli-
ca ions o clinical p ac ice due o he po en ial o epea ed
RET (pa icula ly eccen ic) in ‘exploi ing’ ele a ed in lam-
ma ion o p opo iona ely inc ease muscle g ow h (see also
“Sys emic in lamma ion”).
Apa om signaling ac o changes, CC can induce
long- e m muscle composi ion changes. Fo example, in
mice wi h CC, muscle non-con ac ile issue ( ib osis) was
~ 2.1- old g ea e compa ed o heal hy con ols, bu 2weeks
(4 week−1) o eccen ic RET educed ib osis by 20% (Ha -
dee e al. 2016). Ano he muscle-was ing mechanism du -
ing CC is dys ophin loss wi hou an inhe en gene ic issue,
leading o myo ibe in eg i y impai men s, muscle p o ein
b eakdown and was ing (Acha yya e al. 2005). In con as ,
inc eased muscle in eg in concen a ion can compensa e
o he lack o dys ophin in dys ophic animals by main-
aining muscle mobili y and s uc u e and inc easing mus-
cle mass (Bu kin e al. 2005). In eg in concen a ions in
humans inc ease a e long- e m eccen ic RET (Ma opa-
lias e al. 2021b), bu he e is a lack o in o ma ion ega ding
he e ec s o concen ic RET. We ha e ecen ly epo ed
ha 20–30min o eccen ic RET pe week elici ed la ge
inc eases (in some cases > 30%) in muscle c oss-sec ional
a ea in heal hy men a e only 8weeks (Ma opalias e al.
Jou nal o Cance Resea ch and Clinical Oncology
1 3
2021b). Gi en ha in eg ins sense mechanical ension and
s imula e p o ein syn hesis, inc eased in eg in concen a ion
ollowing eccen ic RET could enhance anabolic signaling,
he eby u he ampli ying muscle g ow h (Bu kin e al.
2005).
Thus, eccen ic RET appea s o be speci ic and po en o
coun e ac ing he mul iple causes o was ing a he myo ibe
le el and could be e y bene icial i inco po a ed as an addi-
ional b ie componen a e a con en ional RET p og am.
Sys emic in lamma ion
Pe sis en ly ele a ed ci cula ing le els o in e leukins,
C- eac i e p o ein (CRP), umo -nec osis ac o alpha (TNF-
α), and in e e on-γ a e hallma k indica o s and p ima y
d i e s o CC (Tisdale 2005; A gilés e al. 2009, 2014).
These umo -d i en cy okines cause mul iple heal h issues,
such as ano exia, and inc eased me abolic a e, lipolysis,
and p o eolysis, among o he s (Tisdale 2005; A gilés e al.
2009, 2014). The e o e, con olling sys emic in lamma ion
is c i ical o CC p e en ion and managemen .
Exe cise is gene ally hough o induce a p o-in lamma-
o y s a e o a ew hou s ollowing a session and hus may
seem con a-indica ed in he p esence o al eady exace ba ed
in lamma ion. Howe e , p o-in lamma o y cy okines, such
as TNF-α and in e leukin-1, do no ma kedly inc ease a e
exe cise, sugges ing ha he exe cise-induced in lamma o y
p o ile di e s om ha induced by disease. In ac , muscle-
de i ed IL-6 ollowing exe cise may inhibi he e ec s o
p o-in lamma o y cy okines such as TNF-α (Pede sen e al.
2001). The e o e, acu e (a ew hou s pos -exe cise) exe -
cise-induced inc eases in cy okine le els do no exace ba e
al eady high-in lamma ion s a es bu may ins ead exe an
in lamma ion-con olling e ec .
IL-6 is a c i ical cy okine o muscle me abolism, as i
media es muscle g ow h demons a ed by bo h in- i o and
in- i o s udies (Se ano e al. 2008). Howe e , when ch oni-
cally ele a ed, ci cula ing IL-6 nega i ely co ela es wi h
myo ibe c oss-sec ional a ea and p o ein syn hesis (Ha -
dee e al. 2020). Exe cise aining can lowe ele a ed IL-6,
as 12weeks (3 week−1) o ei he descending o ascend-
ing s ai -walking in women dec eased es ing IL-6 le els
(−24%) (Chow e al. 2020). In p e-clinical CC models,
muscle g ow h induced by 2weeks (4 week−1) o eccen ic
RET posi i ely co ela ed wi h ci cula ing IL-6 (Ha dee
e al. 2020), such ha highe se um IL-6 was associa ed
wi h g ea e muscle p o ein syn hesis. This sugges s ha
in mice wi h CC, epea ed eccen ic RET migh media e
muscle p o ein syn hesis h ough in lamma ion (g ea e
in lamma ion induces g ea e muscle p o ein syn hesis), a
inding which may hold po en ial o CC pa ien s. I is cu -
en ly unknown i his e ec is induced by concen ic o
con en ional RET, howe e , based on i s abili y o con ol
IL-6 in heal hy women (Chow e al. 2020), pa hways ha
media e p o ein syn hesis h ough ele a ed IL-6 migh also
be ac i a ed du ing concen ic RET.
CRP is he mos p ac ical, cos -e ec i e, and scien i i-
cally obus CC bioma ke , wi h impo an oles in p og-
nosis, and u ili y o p edic quali y o li e in CC pa ien s
(Fea on e al. 2011; Lai d e al. 2016). The esul s o one
me a-analysis we e ha RET educes CRP le els, bu only
when he p og ams included mo e han eigh exe cises, we e
pe o med a leas 3 week−1, and o longe han 12weeks
(Sa deli e al. 2018). Howe e , 1yea o biweekly RET was
also e ec i e in educing CRP le els by ~ 10% in women
(Olson e al. 2007). Rega ding ype, RET ei he wi h eccen-
ic o concen ic mo emen s educed CRP le els (25%) in
seden a y humans, howe e , he au ho s epo ed ha eccen-
ic RET was signi ican ly mo e e icien (~ 2.5 imes) han
concen ic a e adjus ing o ene gy expendi u e (Zeppe -
zaue e al. 2013). Speci ically o cance , a me a-analysis
showed ha a combina ion o RET and endu ance aining
can educe CRP le els (Khos a i e al. 2019). Rega ding
endu ance exe cise, pa ien s wi h di e en cance ypes had
a 6% educ ion in CRP le els a e 12weeks (3 week−1)
o HIIET, bu his was signi ican ly di e en o he LICET
g oup who exhibi ed a 19% inc ease (Toohey e al. 2016).
These indings show a clea bene icial e ec o RET o all
ypes in educing CRP le els in bo h heal hy and cance
pa ien s, howe e , he e appea s o be a p e e ence o HIIET
o e LICET in cance pa ien s, al hough he in o ma ion a
his s age is limi ed.
Ch onically ele a ed TNF-α, bo h ci cula ing and in
muscle, is a common symp om du ing CC, and has been
also shown o be in e sely associa ed wi h muscle p o ein
syn hesis (G eiwe e al. 2001; A gilés e al. 2009, 2014).
Howe e , 3mon hs (3 week−1) o lowe -body RET was
e ec i e in educing TNF-α le els in he muscle o ail
elde ly indi iduals (G eiwe e al. 2001). In ano he s udy,
12weeks (3 week−1) o descending s ai walking (eccen ic
exe cise o knee ex enso s) was mo e e ec i e (−40%)
han ascending s ai walking aining (−24%) a dec easing
TNF-α le els in women (Chow e al. 2020). While esea ch
on humans is limi ed, non-RET endu ance aining can p e-
cipi a e dec eased TNF-α le els, howe e , in ensi y ma e s,
as 8weeks (5 week−1) o HIIET was mo e e ec i e han
LICET in educing TNF-α in mouse enal issue (Lei e e al.
2021).
Ele a ed ci cula ing in e e on-γ is ano he commonly-
obse ed disease sign du ing CC (A gilés e al. 2009).
In e e on-γ is p oduced by ac i a ed T and na u al kille
cells, and animal s udies ha e shown ha inc eased
in e e on-γ p oduc ion apidly de elops CC, and ha CC
can be e e sed by blocking in e e on-γ (A gilés e al.
2009). In elde ly women, 12weeks (3 week−1) o whole-
body ligh -load (elas ic bands) RET educed in e e on-γ
Jou nal o Cance Resea ch and Clinical Oncology
1 3
le els (12%) (Roh e al. 2020). Mo eo e , pa ien s wi h p os-
a e cance dec eased in e e on-γ le els a e only 8weeks
(3 week−1) o RET (Papadopoulos e al. 2021). Al hough
u he in o ma ion ega ding esponses o long- e m exe -
cise aining is cu en ly limi ed, hese esul s a e p omis-
ing and sugges ha e en ligh -load RET migh e ec i ely
educe in e e on-γ le els.
The e o e, RET appea s o be e ec i e in educing
ele a ed TNF-α, CRP, and in e e on-γ, while simul ane-
ously ‘exploi ing’ ele a ed IL-6, ypically obse ed du ing
CC, o inc ease muscle p o ein syn hesis. When combined
wi h HIIET, he in lamma ion-con olling e ec may be
po en ia ed.
Reduced appe i e andano exia
Reduced appe i e and ano exia con ibu e g ea ly o CC,
especially du ing head-and-neck, gas oin es inal, and colo-
ec al cance (F ed ix e al. 1990). In ac , he disease p o-
ile o CC can appea simila o s a a ion, howe e , muscle
was ing o en p ecedes dec eased ene gy in ake, and can
occu e en wi hou ano exia, in bo h humans and animals
(Tisdale 2001).
Bo h acu e sessions and 12weeks (3 week−1) o exe cise
in ol ing eccen ic RET dec eased p e e ence and implici
wan ing o swee oods, bu inc eased p e e ence o a y
oods (Thi el e al. 2020). This migh be pa icula ly bene i-
cial du ing CC, as pa ien s a e u ged o consume an ene gy-
dense die composed o high amoun s o a (A ends e al.
2021). Equi alen concen ic RET inc eased hunge and
desi e o ea mo e han eccen ic, e en hough bo h concen-
ic and eccen ic RET equally inc eased o al ene gy con-
sump ion (Thi el e al. 2020). Specula i ely, due o he lowe
ene gy expendi u e o eccen ic RET (Las ayo e al. 1999),
he inc eased ene gy consump ion migh esul in a highe
ne ene gy balance compa ed o concen ic. These indings
sugges ha eccen ic migh be p e e able o concen ic RET
in simul aneously inc easing p e e ence o ene gy-dense
oods and ene gy consump ion, howe e , i is unknown i
his applies du ing CC.
Rega ding endu ance aining, pos -exe cise appe i e o
adlibi um ene gy consump ion we e unchanged a e a sin-
gle session o ei he LICET o HIIET (Poon e al. 2018).
Howe e , a e 16weeks (5 week−1), bo h LICET and
HIIET, when combined wi h RET, inc eased as ing hunge ,
desi e o ea , and o al ene gy consump ion in adolescen s
(Migue e al. 2020). In ano he s udy, 12weeks (3 week−1)
o ei he HIIET o LICET inc eased as ing and pos p an-
dial eelings o hunge wi h no di e ences be ween ype,
howe e ene gy consump ion was unchanged (Ma ins e al.
2017). One possible eason o his disc epancy is ha he
second s udy did no include RET (Ma ins e al. 2017).
E en hough mo e esea ch is needed, especially du ing
CC, hese esul s sugges ha a combina ion o RET and
endu ance aining migh inc ease hunge and o al ene gy
consump ion.
Inc eased ene gy expendi u e and a was ing
Despi e educed physical ac i i y, ene gy expendi u e
inc eases du ing CC (F ed ix e al. 1990). This hype -
me abolic s a e is hough o occu om a combina ion o
ele a ed in lamma ion and es ing lipolysis (F ed ix e al.
1990). When combined wi h appe i e educ ions, i ine i-
ably leads o a and muscle was ing. Apa om being
ampli ied by he inc eased ene gy expendi u e, a was ing
is p ima ily induced by inc eased lipolysis, as he e is an
inc eased u no e o ee a y acids and glyce ol, caused by
ele a ed TNF-α (Ma hu and Pede sen 2008; Tisdale 2009).
Exe cise inc eases ene gy expendi u e; hus, CC manage-
men should include exe cise modes ha p omo e muscle
g ow h wi h he lowes ene gy expended.
Endu ance aining has almos double he ene gy expendi-
u e compa ed o RET, when ma ched o ela i e in ensi y
(Bloome 2005). Mo eo e , due o i s capaci y o induce
whi e adipose issue b owning, mi ochond ial biogenesis,
a loss, and he mogenesis, which a e exis ing p oblems
du ing CC (G gic e al. 2019), LICET is less op imal du -
ing CC. Su p isingly, ecen e iews ecommended endu -
ance aining o e RET o educe muscle was ing du ing CC
(Aquila e al. 2020). Howe e , due o he abo e-men ioned
con a-indica ions, LICET may be subop imal agains mus-
cle was ing du ing CC. Ne e heless, in some cases, e en
highe -in ensi y endu ance aining modali ies o sho e
du a ions may be bene icial. Fo example, in mice wi h CC,
10weeks o highe -in ensi y con inuous endu ance exe -
cise (5 week−1, 30min/day, 85% VO2max) inc eased li es-
pan, educed umo mass, and p e en ed educ ions in o al
body a (Bacu au e al. 2007). Howe e , he e is a lack o
in o ma ion on endu ance aining in e spaced wi h es on
ene gy expendi u e in CC pa ien s. In e es ingly, in heal hy
unne s eplacing LICET wi h HIIET did no impai ae obic
capaci y o muscle oxida i e capaci y, bu dec eased ene gy
expendi u e du ing unning (Iaia e al. 2009); howe e , hese
esul s may di e du ing CC. The e o e, HIIET could be
bene icial du ing CC, bu p io i y should be gi en o RET
when aiming o inc ease muscle mass wi h lowe ene gy
expendi u e.
Rega ding RET ypes, du ing eccen ic RET he same
muscle wo k can be p oduced wi h only ~ 15% o he me a-
bolic demand, while ca dio ascula demand is ~ 40% less
when compa ed o concen ic RET (Las ayo e al. 1999).
These cha ac e is ics a e a ac i e o implemen a ion du -
ing CC, as eccen ic RET can s imula e muscle hype ophy
bu wi h much lowe ene gy expendi u e.
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Publishe 's No e Sp inge Na u e emains neu al wi h ega d o
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