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CURRENT
OPINION Age-related and cancer-related sarcopenia: is there
a difference?
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Federico Bozzetti

Purpose
The aim of this review is the attempt to differentiating the pathophysiologic and clinical features of the
aging-related sarcopenia from cancer-related sarcopenia. In fact, there is some controversy among the
experts mainly regarding two points: is always sarcopenia, even that aging-related one, the expression of
a generalized disease or may exist independently and without major alteration of the muscle function? Are
always aging-related and cancer-related sarcopenia completely separated entities?
Recent findings
Literature shows that sarcopenia, defined as simple skeletal muscle mass loss, may range from a mainly
focal problem which is common in many healthy elderly people, to a component of a complex multiorgan
syndrome as cancer cachexia. Disuse, malnutrition and (neuro)degenerative processes can account for
most of the aging-related sarcopenias while systemic inflammation and secretion of cancer-and immune-
related molecules play an additional major role in cachexia.
Summary
A multimodal approach including physical exercise and optimized nutritional support are the key measures
to offset sarcopenia with some contribution by the anti-inflammatory drugs in cancer patients. Results are
more promising in elderly patients and are still pending for cancer patients where a more specific
approach will only rely on the identification and contrast of the key mediators of the cachectic process.
Keywords
age-related sarcopenia, cancer-related sarcopenia, fibres atrophy in sarcopenia, inflammation in sarcopenia,
multimodal therapy in sarcopenia

INTRODUCTION such approach should be abandoned. In fact, such

Originally characterized as loss of muscle mass concept would not hold anymore because LMM is
(LMM), the definition of sarcopenia has evolved to always related to some paraphysiological or patho-
focus on muscle mass function because it soon logical condition as aging, malnutrition, or
became evident that muscle strength was a better wasting syndromes.
predictor of outcome. Consequently, around 2010, However, these statements are somewhat ques-
&
several definitions were proposed [1 ], adding muscle tionable.
function and strength to LMM through several inter- A study [4]. on 1073 “healthy” subjects (median
national definitions such as that of the European age and BMI being 51 years and 25.4 kg/m2, respec-
Working Group on Sarcopenia in Older People tively) reported that the prevalence of LMM was
& &
[1 ,2 ]. Part of the discrepancy in the definition of 13.3% in subjects aged 18–39, 54.4% in subjects
sarcopenia between the gerontologic and oncologic aged 40–59, and 32.4% in those aged
60.
literature exists because of the different viewpoints Similarly, all cancer patients, regardless of the
and outcomes under consideration. Geriatrics views presence of other symptoms of cachexia, may be
sarcopenia in the light of developing disability,
whereas oncology has focused more on low muscle
mass and its association with increased mortality and Residenza Querce, Milanodue, Segrate, Italy
complications from cancer treatments. Correspondence to Federico Bozzetti, Residenza Querce, Milanodue,
& &
According to some authorities [1 ,3 ]. the fact 20054 Segrate, Italy. Tel: +39 32755385;
that sarcopenia is still used with two different mean- e-mail: [email protected]
ings (LMM or LMM plus low muscle function) is Curr Opin Clin Nutr Metab Care 2024, 27:000–000
causing confusion to researchers and clinicians and DOI:10.1097/MCO.0000000000001033

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cancer (65 years or later) which overlaps with age

KEY POINTS which defines people as elderly.
In this short review I will address the two major
 Sarcopenia may be the only sign of elderly patients.
topics: the myopenia of the elderly and of cancer
 All losing-weight subjects have a loss of skeletal patients, this latter being artificially distinguished in
muscle mass. cancer-related sarcopenia and sarcopenia due to
systemic cancer therapy.
 Pathophysiology of age-related and cancer-related
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sarcopenia is different.
 Sarcopenia of the cancer patient may be a component AGE-RELATED SARCOPENIA
of a multiorgan syndrome.
Epidemiology
 Response to treatment is better in age-related
sarcopenia as compared with cancer- It is well known that, from the age of 30, muscle mass
related sarcopenia. decreases by around 3–8% per decade and this
decrease accelerates after the age of 60. Indeed, after
the age of 70, the muscle mass declines by 0.5–1.0%
per year, the decline being different by sex, close to
sarcopenic if they lose weight. Studies have shown 1% per year in men and 0.7% per year in women after
that in losing-weight subjects because of a voluntary 75 years, with an even steeper decline in muscle
calorie restricted diet, the percentage of lost muscle strength of 3–4% in men and 2.5–3% women.
mass represents about 10% [5,6], and 23% and 10% Recently, Cameron et al. [10] showed that over 5-year
in males and females, respectively in a large series period healthy septuagenarians lost about 4.5–5% of
&
reported by Heymsfield et al. [7 ]. their appendicular lean muscle mass and Teraz et al.
For the purpose of this study, we will attempt to [11] reported a 4.5% decrease of skeletal muscle index
compare sarcopenia of the aging subjects and cancer over an 8 period of follow up of 69 healthy and active
patients, regardless of the presence of all those older adults (mean baseline age 68.3 years). It is wor-
symptoms which can characterize the clinical pic- thy of note that, however, the age-related changes are
ture of frailty or of the cancer cachexia, respectively, not uniform across all muscles and the extent of
and we will generally refer for the definition of sarcopenia varies between muscles in different loca-
“sarcopenia” or “myopenia” to a total muscle mass tions with different functions.
<2 standard deviations below the mean for young The prevalence of sarcopenia increases with age, is
(18–39 years) healthy reference populations. generally greater in men, in hospitalized patients and
Even so, multiple causes often overlap in these in nursing home resident versus community-dwelling
subjects’ populations which can be affected, even at a older adults. If we consider healthy people
60 years a
subclinical level, by endocrine, inflammatory, neuro- low skeletal muscle index is reported in 32.4% of
logic, hematologic diseases and organ failures. Like- subjects [4]. and, more precisely, according to a sys-
wise all these subjects can be exposed to a number of tematic review and meta-analysis [12]. the highest
activity-related conditions (bedridden state, hospital- prevalence estimates were for the appendicular lean
ization, institutionalization, prolonged weightless- mass (ALM)/weight (40.4%), ALM/height (30.4%),
ness, sedentary lifestyle, socioeconomic status, ALM regressed on height and weight (30.4%) and
smoking), nutrition-related conditions (alcohol ALM/BMI (24.2%) definitions. A study in Northern
excess, low body weight, low protein intake, low fat- Italy on subjects attending a metabolic rehabilitation
soluble vitamin intake, malabsorptive conditions) and unit found that the prevalence of sarcopenia in old
medication-related conditions (glucocorticoid ther- (66–84 years) and oldest old (>84 years) was 35.3%
apy, oncologic drugs, heparin, antiepileptics, aroma- (males), 10.3% (females) and 53.7% (males), 18%
tase inhibitors, GnRH agonists, excess thyroxine) that (females), respectively [13]. These findings are in keep-
play a transversal additional role in the pathophysi- ing with the global prevalence 27% estimated in 33
246 >60 years individuals [14 ].
&& &
ology of sarcopenia [8,9 ]. Finally, men have a greater
LMM than women, even though this gross difference
can be partly explained by the greater initial muscle
mass of men, and discrepancy of the gender distribu- Pathophysiology
&&
tion in different series makes difficult comparison As recently summarized by Granic et al. [15 ] at the
between studies. cellular level, some hallmarks of skeletal muscle
A further problem, when one attempts to dis- ageing include increased myofiber variability,
entangle the sarcopenia of elderly subjects from that decreased myofiber cross-sectional area (known as
of the cancer patients, is due to the peak age of atrophy) and functional denervation of myofibers

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due to the alteration of the neuromuscular junctions. are increased in sarcopenic patients: CPR [23], inter-
There is a preferential atrophy and loss of type IIb leukin (IL)-8, sTNFr-1, and sTNFr-2 in women [24],
myofibers which are the fast glycolytic muscles, have TNF-a [25]. IL-6 appears variously increased or
a low supply of oxygen, use anaerobic respiration to decreased depending on the research [25]. High
support quick, powerful movements such as sprint- levels of reactive oxygen species (ROS) can finally
ing or weightlifting, and therefore very little mito- cooperate in dysregulation of signalling pathways
chondria. They contain very few myoglobin and oxidative damage to mitochondria, proteins,
molecules and therefore appear white. Many of these lipids, RNA and DNA in muscle cells, contributing
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fast myofibers become denervated and are re-inner- to muscle atrophy and sarcopenia [26,27]. A recent
vated by slow motor neurons (type I myofibers). This study [24]. on 437 sarcopenic subjects (average age
process is potentiated by the exercise [16], so these of 70.4  4.8 years) reported that IL-6 displayed a
fibres finally survive but lose their original identity. negative correlation with thigh muscle volume but
This loss of type IIb myofibers and neuromuscular demonstrated a positive correlation with thigh fat
junction remodelling is considered a key feature of volume and innate immunocyte (natural killer, NK
skeletal muscle ageing. The consequence is the cells) displayed positive correlations with total thigh
decline in skeletal muscle strength with age and volume and total muscle volume. Similarly adaptive
especially in females, as evident by the observation immunocyte (T or B cells) showed positive correla-
that older individuals and females have a greater tions with total muscle volume and negative corre-
proportion of type I myofibers along with lower lations with total fat volume.
strength fast-twitch type IIb muscle fibres. The drop of other mediators as brain-derived
An excellent review [17]. critically reviewed the neurotrophic factor (BDNF), dehydroepiandroster-
biochemical markers of musculo-skeletal health and one sulphate, testosterone and vitamin D may play a
aging associated with sarcopenia and reported that role in geriatric sarcopenia [29,30].
the nine classic hallmarks of contribute to skeletal Altered levels of GDF15 associated with aging in
muscle ageing and the pathophysiology of sarcope- humans – higher in older men than in age-match-
nia. They should be: genomic instability, telomere ing women – were proposed as causative of both
attrition, epigenetic alterations, loss of proteostasis, sarcopenia and the low physical performance of
deregulated nutrient sensing, mitochondrial dys- the muscle.
function, stem cell exhaustion, and altered intercel-
lular communication. Senescent cell especially
would create an aged-like inflamed niche that mirrors Therapy
inflammation associated with ageing (inflammage- While the modern treatment of geriatric sarcopenia
ing) and arrests stem cells proliferation and regener- relies on a combined nutrition- and exercise-based
ation [18]. To these markers, the authors [17]. add five approach, for practical reasons in every-day life
novel hallmarks of particular significance to skeletal some patients may receive only one of them.
muscle ageing: neural dysfunction, extracellular
matrix dysfunction, reduced vascular perfusion,
and ionic dyshomeostasis and inflammation. Nutritional therapy
Recent research on mediators involved in the Evidence from randomized controlled trial (RCT)
pathogenesis of geriatric sarcopenia found that both has been accumulating for the beneficial effects of
&
the circulating irisin concentrations [19 ]. as well as nutritional supplements containing whey protein
&
the muscle gene expression of IGF-1 [20]. were (with or without vitamin D) [31 ]. or omega-3 fatty
&
attenuated while that of myostatin was unchanged acid [32 ]. or branched-chain amino acid [33].
[21]. or decreased. Jiang et al. [22] however, reported Observational studies would favour animal versus
that serum IGF-1 levels were associated with sarco- plant protein sources for sarcopenia related param-
&&
penia in elderly men but not in elderly women. eters [34 ]. A protein consumption above the Rec-
Coupled with no change in some IGF-1 isoforms, ommended Daily Allowances (RDA) (about 1.6 g/kg/
IGF-IEA and IGF-1EC/MGF, increased GDF-15 day) is recommended for older adults, as this intake
&
expression and the attenuation of genes responsible appears beneficial in attenuating sarcopenia [2 ].
for protein degradation (Atrogin, Murf-1, FoXO3 There are two recent systematic reviews and
and LC3), the emerging picture is suggestive of a meta-analyses on the potential effects of nutrients
&
somewhat preserved balance between pro- and in sarcopenic subjects: Chang et al. [35 ] showed
antiatrophy factors. that the appendicular muscle mass significantly
Low-grade chronic inflammation present dur- increased by the whey protein, leucine, and vitamin
ing ageing also contributes to disturbed proteostasis D supplementation but, only when combined with
and muscle atrophy. Some inflammatory mediators physical exercise, there was also a significant

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improvement in the handgrip strength and short These beneficial effects are achieved through the
physical performance battery scores. Similarly, modulation of myokine and adipokine tissue
&
Kwon et al. [36 ] reported that nutritional supple- expression and secretion and generally take weeks
mentation group exhibited significant improve- to months before training-induced changes in skel-
ment in appendicular skeletal muscle mass while etal muscle mass become apparent. In fact, insulin
handgrip strength and short physical performance resistance, commonly observed in older adults, can
battery only showed a tendency for improvement. impact IGF-1 signalling and contribute to anabolic
The majority of the included RCTs provided extra resistance [45]. The prolonged time course for
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protein supplements with amounts of whey protein hypertrophy reflects the slow turnover rate of
ranging from 10.0 to 40.0 g/day, one used leucine muscle proteins, which is about 1% per day for
(1 g/day), arginine (1.5 g/day), and vitamin-D 300 IU contractile proteins [46].
complex/day without whey protein. Vitamin D Prolonged RT in old men resulted in a significant
doses ranged from 600 to 1600 IU/day. A further increase in type II fibre size with no significant
systematic review and meta-analysis by Guo et al. changes in the proportion of type I muscle fibres
&
[37 ] reported that leucine-isolated supplementa- found grouped [47]. Finally, a recent RCT [48] in
tion did not improve muscle mass and strength in elderly subjects (average 72 years) has shown that
elderly. However, leucine-combined supplementa- fast walking significantly increased the number of
tion including vitamin D exhibited a significant helper T cell, while slow and moderate walking
benefit for muscle strength and performance includ- increased the number of the natural killer cell.
ing handgrip strength and gait speed in older adults. It is worth to be mentioned that endogenous
testosterone sufficiency has a central role in the up-
regulation of molecular transducers of RT-induced
Exercise to improve the muscle mass muscle hypertrophy in humans that cannot be over-
Most trials evaluated the benefits of two main come by muscle mechano-transduction alone [49].
modalities of physical exercise training: endurance
(ET) and resistance training (RT). ET, also known as
aerobic or cardio exercise, consists of activities Combined nutritional therapy and exercise
where large muscles move in a rhythmic manner At least five systemic reviews and meta-analysis
& & & &
and for a sustained period, such as walking, running, [31 ,36 ,50 –52 ]. have been published in 2023.
and swimming and results in increases in heart rate Apart from the already quoted paper by Kwon
& &
and energy expenditure. et al. [36 ], Nasimi et al. [31 ] found that whey
RT promotes progressive overload to skeletal protein supplementation increased lean mass, when
muscles, improving their strength and promoting combined with RT, in sarcopenic or frail older
hypertrophy, and intensity, while frequency and adults. Whey protein supplementation did not
repetitions may vary. affect muscle strength, but improvements were seen
Physical activity and/or structures exercise are with higher doses of whey (>20 g) when combined
now recommended by the Expert Consensus Guide- with RT. Longer duration (>12 weeks) whey protein
lines [38]. supplementation significantly improved physical
RT can achieve an increase of the lean body mass function, particularly grip strength, but the addition
in older adult overweight subjects, changes being of RT superseded the effects of the protein supple-
equivalent to a relative increase of 2.4% [39]. Recent mentation and supplementation provided no fur-
evidence suggests that a RT programme consisting ther benefit. Similarly, the meta-analysis by Song
&
of at least two exercise sessions per week with a et al. [50 ] reported that vitamin D and protein
combination of upper and lower-body exercises increased grip strength and gait speed whereas RT
performed with a relatively high degree of effort alone was ineffective. These findings are in keeping
for 1–3 sets of 6–12 repetitions is effective as a with meta-analyses focusing on the efficacy of
treatment for sarcopenia [40]. RT can involve using muscle-targeted oral nutritional supplementation
where a dietary protein intake >1 g/kg/day [51 ].
&
resistance machines, free weights, bodyweight exer-
&
cises, and resistance bands [40]. or leucine [52 ] is recommended.
In sarcopenic patients too, exercise has shown
translational potential for treating myopenia, by
possibly attenuating several hallmarks of ageing SARCOPENIA IN CANCER
including macromolecular damage, dysregulated Although image analyses indicate that skeletal
stress response, disruption in proteostasis, meta- muscle depletion varies from 7% to 30% in cancer
bolic dysregulation, epigenetic drift, inflammaging, cachexia [53], all patients who are losing weight
& &
and stem cell exhaustion [16,41 ,42,43,44 ]. have, to a variable extent, a LMM since previously

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quoted studies (5–7) have shown that muscle pro- RCT in patients who had weight loss >5% in the last
tein loss represents an obligatory component of the 6 months receiving a specific high-calorie, high-
body weight loss due a dietary restriction. If a can- protein oral nutritional supplements enriched with
cer-related hypoanabolic reaction is superimposed leucine, EPA, DHA, and b-glucans or an isocaloric,
to a condition of starvation, muscle depletion isonitrogenous standard oral supplements for
is amplified. 8 weeks, showed a significant increase in muscle
LMM in cancer patients affects glycolytic (red) mass, which was not detected with the standard
fibres I to a greater extent than oxidative ones and is oral supplements [60].
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consistent with the fact that cachexia is more severe

in men where glycolytic fibres are more abundant in
men than in women who have a higher number of Physical exercise
oxidative fibres. There are intracellular alterations Available evidence shows that patients with cancer-
including a drop in ribosomal gene transcription related sarcopenia can safely undertake higher-
and consequently a selective ribosome degradation intensity RT programs, and benefit from increases
by the autophagy–lysosome pathway [54]. in body mass and muscle mass [61].
Recent research is uncovering a myriad of factors The exercise interventions include ET (repeated
that contribute to the pathophysiology of LMM isotonic exercises that last in time to improve aero-
acting both in concert but also independently from bic capacity) and RT (exercises training muscles
the presence of inflammatory mediators. As against an external force, usually shorter than
&&
reported by Kadakia et al. [55 ] in an excellent endurance training). Although more studies are
review, a complex mix of tumour-derived catabolic needed to assess the effect of a high intensity inter-
factors and proinflammatory mediators, generated val training (HIIT) protocol on cachexia-induced
through tumour crosstalk with the immune and muscle loss, current guidelines state that a pro-
stromal cells of the microenvironment, contributes gramme of HIIT is safe, tolerable, and effective as
to initiating the cachexia process. These tumour- part of a comprehensive cancer rehabilitation pro-
derived factors as recently summarized by Talbert gram [62]. Interestingly in patients with breast can-
et al. [56], include activin [57], ActRIIB ligand, adre- cer undergoing chemotherapy, high intensity
nomedullin, GDF15, heat shock protein 70/90, exercise resulted in a lesser increase of C-reactive
miR21, parathyroid hormone-related protein, zinc protein (CRP) and tumour necrosis factor alpha
alpha2 glycoprotein, and microRNAs. The products (TNF-a) immediately posttreatment compared to
of tumour cells-immune system crosstalk include low-moderate intensity, potentially protecting
INF-gamma, IL-1 a/b, IL-6, IL-11, IL-17, leukocyte against chemotherapy-related inflammation [63].
inhibitor factor, lipocalin2, prostaglandin TNF-a, Papadopetraki et al. [64] in their review emphasize
TRAF6, TNFRSF, TWEAK 12A. Furthermore, cancer that the supervised exercise programs were well
cells can exert systemic effects partly because they tolerated by cancer patients and the adherence
secrete extracellular vesicles that can travel through ranged from 68.2% to 95%, and 26.2% of the
the circulation and deliver bioactive molecules, patients reversed their sarcopenia status and con-
including miRNAs and proteins, to various organs, sequently improved their self-reported quality of life
including muscle [58,59]. Then, it would appear that and fatigue. Furthermore, they favour exercise
pathophysiology of cachexia expands beyond the under supervision compared to the home-based
boundaries of a simple inflammatory reaction. unsupervised exercise training.
The rationale for exercise intervention has been
recently summarized by Torregrosa et al. [65]. ET
Nutritional therapy enhances skeletal muscle mitochondrial activity,
Traditionally, the literature [53]. reports the poten- increases the expression of PGC-1 without a major
tial nutritional interventions include an adequate impact on the skeletal muscle size, increases the
energy supply (25–30 kcal/kg/day) and administra- activity of AMPK and calcium- and calmodulin-acti-
tion of protein (1.0–1.5 g/kg/day) and, furthermore, vated protein kinase, which, in turn, activates the
various combinations of branched-chain amino peroxisome proliferator-activated receptor coactiva-
acids (leucine: 2–4 g/day), b-hydroxy b-methylbu- tor-1 pathway and facilitates the mitochondrial bio-
tyrate (3 g/day), glutamine (0.3 g/kg/day), carnitine genesis. RT, especially, can increase protein
(4–6 g/day), creatine (5 g/day), fish oil/eicosapen- synthesis and activate the mTORC1 pathway, an
taenoic acid (2.0–2.2 g/day EPA and 1.5 g/day important mechanism for muscle hypertrophy.
DHA), vitamin/minerals (e.g. vitamin D: 600– In addition, exercise reduces inflammation [66]
800 UI/day). However, despite such approach, there and prevents myocyte autophagy. Plasma levels of
is a blunted anabolic response to feeding. Recently, a free amino acids are reduced with exercise while

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proteins in fast-twitch skeletal muscle fibres literature has called for a better standardization of
are increased. the studies with regard the selection of homogenous
These effects are mediated by an increase in cohorts, clear definition of baseline/endpoint tim-
&
meteorin-like, follistatin, decorin, irisin, BDNF, ing and attention to measurement errors [71 ]. A
but also in cytokines, such as IL-6 and miRNAs. recent meta-analysis [72]. investigated the amount
Exercise leads to an increase in anti-inflammatory of LMM during the neoadjuvant therapy and found
cytokines, in insulin sensitivity, in glucose tolerance a 10% mean loss, the highest values being seen
and in fat browning, but a downregulation of the among patients with pancreatic cancers on leuco-
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TNF-a and IL-1. Myostatin synthesis and secretion is vorin, fluorouracil, irinotecan and oxaliplatin, and
decreased during exercise, causing a decrease in in patients receiving neoadjuvant chemoradiation
muscle differentiation and muscle fibre protein (including cisplatin plus fluorouracil or docetaxel)
accretion. Bordignon et al. [67] emphasize that for head and neck or oesophageal cancers or patients
although IL-6 is involved in pro-inflammatory undergoing therapy with leucovorin, fluorouracil
events such as sepsis, during exercise it acts as an and oxaliplatin for cancer of stomach or of the
anti-inflammatory promoter. IL-6, induced by phys- gastroesophageal function. These treatments pro-
ical activity, is considered a myokine which stim- duced an 8% to 14% LMM over 100 days of therapy.
&&
ulates the production of IL-1ra and IL-10 (which are Kadakia et al. [55 ] speculated that a 10% LMM
anti-inflammatory cytokines), and inhibits TNF-a, a would approximately correspond to that due to
pro-inflammatory cytokine. aging 20 years in men and 25 years in women, that
It is noteworthy that most of the international is iatrogenic sarcopenia exhibits a muscle catabo-
guidelines recommend exercise to cancer patients lism 70–90 higher than the physiologic one. It is
who are suffering from fatigue to improve this worthy of note that a recent study reported that
symptom [68]. standard palliative chemotherapy regimens contrib-
ute to muscle wasting in advanced cancer patients
independent of tumour response and patients, with
Combined nutritional therapy and exercise the most muscle or fat loss by tertiles had 72–73%
It is worth mentioning that superior effects might be greater hazard of death compared to those with the
achieved by multimodal nutritional interventions, smallest losses [73]. Mallard et al. [74] demonstrated,
which combine the administration of various in 11 patients receiving chemotherapy for early-
nutrients [69]. and to this approach is addressing stage breast cancer, major mitochondrial altera-
the current clinical research. Nowadays there are at tions, including reduced mitochondrial increase
least three ongoing phase II and III randomized in the initiation of apoptosis. By Vanderven et al.
clinical trials on multimodal therapy, also including [75] monotherapy with 5-fluorouracil decreased
anti-inflammatory or orexigenic drugs, in weight- muscle mass and perturbed skeletal muscle immune
losing cancer patients [67]. cells and impaired infiltration following damage
contributing to disrupted muscle repair.

SARCOPENIA DUE TO SYSTEMIC CANCER

THERAPY Pathophysiology
I felt necessary to include a section devoted to the There are several classes of systemic cancer therapy
iatrogenic sarcopenia, because old and new cyto- intended to inhibit tumour cell proliferation which
toxic and biologic agents can have a deep impact on can affect skeletal muscle. Some mechanisms for the
muscle metabolism. It is obvious, however, that, myotoxicity are being unravelled by the current
when referring to human studies all findings cannot research and probably differ by class of oncologic
be attributed to the adverse effects of the therapy but drug.
also to the anomalous metabolic response of a
tumour-bearing host. (1) Cytotoxic chemotherapies (including alkylating
Systemic oncologic therapies, cytotoxic, tar- agents, topoisomerase inhibitors, antimetabo-
geted or immunotherapies, can provide an addi- lites, mitotic inhibitors) damage differentiated
tional impetus to the catabolic drive. This topic muscle cells because they alter DNA replication
has been recently summarized by in an excellent and translation and control the cell cycle and
&&
review [70 ]. The common oncologic approach inhibit muscle stem cell proliferation. Cisplatin
through the neoadjuvant chemotherapy has pro- is the most intensively studied individual com-
vided the opportunity of evaluating the status of pound [76–80]. and would act in double way:
the muscle mass prior and after the treatment. How- inhibiting protein synthesis and eliciting pro-
ever, the high heterogeneity of results reported in tein degradation. The suppression of protein

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Age-related and cancer-related sarcopenia: is there a difference? Bozzetti

synthesis would occur through an Akt protein drugs including docetaxel, cis-platinum, 5-fluorour-
kinase B (Akt)-dependent mechanism and con- acil [87]. or carboplatin/paclitaxel or 5-fluroura-
sequent p70S6k1 dephosphorylation. Coupled cilþleucovorin, oxaliplatin [88].
with the inhibition of mTORC1 there is an acti-
vation of the forkhead boxO (FoxO)-dependent
signalling cascades, enhancement of the tran- CONCLUSION
scription of atrogins (e.g. MuRF-1, Atrogin-1), There are quantitative and qualitative differences
and a synergistic activation of the ubiquitin pro-
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between age-related and cancer-related sarcopenia,

teasome system and autophagy, that result in the latter usually being more severe and less respon-
myofibrillar degradation. In addition, H2O2 pro- sive to nutrition- and exercise- based approaches.
duction, and oxidative stress alter the Ca2þ
Differences are more relevant if we compare, for
dynamics which regulates diverse cellular func- instance, the LMM of young cachectic man with a
tions, such as enzyme activation, muscle con-
pancreatic carcinoma (receiving or not chemother-
traction, cell differentiation and consequent
apy), with a similar LMM of a 70-year-old woman
reduced force production and fatigue. The
who is healthy and perfectly able to ride a bicycle.
administration of 5-fluorouracil in mice [81].
On the contrary, differences tend to blunt if we
was shown to disrupt skeletal muscle immune
compare elderly males with cancer with elderly non-
cells (CD45þ immune cells, especially infiltrating
cancer males with severe comorbidities which per se
CD11bþ Ly6cHi monocytes and CD11bþ CD68þ
can cause LMM.
macrophages) and impairs muscle repair and The pathologic picture is different in age-related
remodelling. The effects of a course of adriamy-
and cancer -related sarcopenia: aging is associated
cin-cyclophosphamide paclitaxel regimen in
with a prevalent loss of fibres II that agrees with the
humans was investigated [82]. through multiple
capacity which many elderly people maintain to
sequential biopsies of the vastus lateralis muscle
take long walks while they cannot pick their teen-
and showed changes in mitochondrial biogene-
ager grandchild up, on the contrary, fibres I are
sis, mitochondrial dynamics and mitophagy as
atrophied in weight-losing cancer patients and
well as fatty infiltration [83]. Interestingly such
hence they can feel promptly exhausted after a
LMM was undetectable by CT [84–86]. minimal physical effort (so-called fatigue).
(2) Targeted therapies include bevacizumab, an
Aging is typically associated with a moderately,
anti-VEGF and cetuximab or panitumumab, an
albeit relevant, increased level of inflammation,
anti-EGFR which are effective in RAS and BRAF
even though it is not clear according to some
wild-type tumours only. They inhibit the intra- &
author [89 ] whether the so-called “inflammaging”
cellular signal transduction pathways involved is a cause or an effect of aging. Notably, reduced
in growth factor mediated cell proliferation, such physical activity is associated with muscle atrophy
as phosphatidylinositol 3-kinase (PI3K), serine/ and bed rest and anorexia per se induce a small rise
threonine-specific protein kinase (Akt) and in pro-inflammatory cytokines as IL-6. On the con-
mammalian target of rapamycin (mTORC-1). trary, systemic inflammation accompanied by
(3) Immune checkpoint inhibitors target receptors increased circulation of proinflammatory cyto-
on immune cells, such as T cells, that regulate kines is an important feature of the advanced can-
immune reactions (e.g., PD-1, CTLA-4 and cer and wasting syndromes and significantly
the ligand PD-L1). Musculoskeletal side effects contributes to LMM and the development of cancer
of immune checkpoint inhibitors include cachexia. In this case sarcopenia is only a compo-
immune-mediated myopathy, myalgia and myo- nent of a complex multiorgan syndrome as well
sitis, myasthenia gravis, and finally necrotizing &&
reported by Kadakia et al. [55 ], whereas LMM may
myopathy. be the only clinical presentation of the age-related
sarcopenia [28].

Therapy Acknowledgements
There are few studies regarding the potential treat- I am indebted with BF for the invaluable help in retriev-
ment of the iatrogenic myopathy, most of them ing the pertinent literature, scrutinizing the papers, and
were done in animal models. The limited clinical identifying the issues which are appropriate for this
experience seems to support the benefit of the exer- updated review
cise [87]. or of the multimodal prehabilitation [88].
to mitigate the CT-defined LMM in patients under- Financial support and sponsorship
going neoadjuvant chemotherapy with a variety of None.

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Hot topic

20. Xu B, Guo Z, Jiang B, et al. Factors affecting sarcopenia in older patients with
Conflicts of interest chronic diseases. Ann Palliat Med 20220; 11:972–983.
There are no conflicts of interest. 21. Wilhelmsen A, Stephens FB, Bennett AJ, et al. Skeletal muscle myostatin
mRNA expression is upregulated in aged human adults with excess adiposity
but is not associated with insulin resistance and ageing. Geroscience 2023;
46:2033–2049.
REFERENCES AND RECOMMENDED 22. Jiang JJ, Chen SM, Chen J, et al. Serum IGF-1 levels are associated with
READING sarcopenia in elderly men but not in elderly women. Aging Clin Exp Res 2022;
34:2465–2471.
Papers of particular interest, published within the annual period of review, have 23. Samson LD, Buisman AM, Ferreira, et al. Inflammatory marker trajectories
been highlighted as: associated with frailty and ageing in a 20-year longitudinal study. Clin Transl
& of special interest
Ho4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 03/18/2024
Downloaded from http://journals.lww.com/co-clinicalnutrition by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsI

Immunol 2022; 11:e1374.

&& of outstanding interest
24. da Costa Teixeira LA, Avelar NCP, Peixoto MFD, et al. Inflammatory biomarkers
at different stages of sarcopenia in older women. Sci Rep 2023; 13:10367.
1. Sayer AA, Cruz-Jentoft A. Sarcopenia definition, diagnosis and treatment: 25. Ying L, Zhang Q, Yang YM, Zhou JY. A combination of serum biomarkers in
& consensus is growing. Age Ageing 2022; 51:afac220. elderly patients with sarcopenia: a cross-sectional observational study. Int J
An authoritative paper focusing on classification of sarcopenia. Endocrinol 2022; 2022:4026940.
2. Coletta G, Phillips SM. An elusive consensus definition of sarcopenia im- 26. Maldonado E, Morales-Pison S, Urbina F, et al. Aging hallmarks and the role of
& pedes research and clinical treatment: a narrative review. Ageing Res Rev oxidative stress. Antioxidants (Basel) 2023; 12:651.
2023; 86:101883. 27. Jackson MJ, Pollock N, Staunton C, et al. Redox control of signalling responses
A paper that well describes the implications of lack of consensus on the definition to contractile activity and ageing in skeletal muscle. Cells 2023; 11:1698.
of sarcopenia. 28. Heo SJ, Park S, Jee YS. Navigating the nexus among thigh volume, myokine,
3. Cruz-Jentoft AJ, Gonzalez MC, Prado CM. Sarcopenia6¼low muscle mass. Eur and immunocytes in older adults with sarcopenia: A retrospective analysis in a
& Geriatr Med 2023; 14:225–228. male cohort. Arch Gerontol Geriatr 2024; 117:105273.
A criticism to the current confused terminology about sarcopenia. 29. Bollen SE, Bass JJ, Fujita S, et al. The Vitamin D/Vitamin D receptor (VDR) axis
4. van Vugt JLA, van Putten Y, van der Kall IM, et al. Estimated skeletal muscle in muscle atrophy and sarcopenia. Cell Signal 2022; 96:110355.
mass and density values measured on computed tomography examinations in 30. K€ oller M. Sarcopenia-a geriatric pandemic: a narrative review. Wien Med
over 1000 living kidney donors. Eur J Clin Nutr 2019; 73:879–886. Wochenschr 2022; 172:5–6.
5. Og»odek E, Pilis Prof W. Is water-only fasting safe? Glob Adv Health Med 31. Nasimi N, Sohrabi Z, Nunes EA, et al. Whey protein supplementation with or
2021; 10:21649561211031178. & without vitamin D on sarcopenia-related measures: a systematic review and
6. Dai Z, Zhang H, Wu F, et al. Effects of 10-day complete fasting on physio- meta-analysis. Adv Nutr 2023; 14:762–773.
logical homeostasis, nutrition and health markers in male adults. Nutrients Excellent review and meta-analysis on supplementation with whey protein and/or
2022; 14:3860. with vit D.
7. Heymsfield SB, Yang S, McCarthy C, et al. Proportion of caloric restriction- 32. Cornish SM, Cordingley DM, Shaw KA, et al. Effects of omega-3 supplementa-
& induced weight loss as skeletal muscle. Obesity (Silver Spring) 2023; & tion alone and combined with resistance exercise on skeletal muscle in older
32–40. doi:10.1002/oby.23910. adults: a systematic review and meta-analysis. Nutrients 2022; 14:2221.
A large study showing that losing weight is always associated with skeletal muscle An exhaustive review with meta-analysis on the topic omega-3 supplementation
mass depletion. and physical exercise.
8. Yuan S, Larsson SC. Epidemiology of sarcopenia: prevalence, risk factors, 33. Peng LN, Yu PC, Hsu CC, et al. Sarcojoint1, the branched-chain amino acid-
and consequences. Metabolism 2023; 144:155533. based supplement, plus resistance exercise improved muscle mass in adults
9. Kuzuya M. Drug-related sarcopenia as a secondary sarcopenia. Geriatr aged 50 years and older: a double-blinded randomized controlled trial. Exp
&& Gerontol Int 2024; 24:195–203. Gerontol 2022; 157:111644.
Excellent review, complete and fully updated. 34. Campbell WW, Deutz NEP, Volpi E, Apovian CM. Nutritional interventions:
10. Cameron J, McPhee JS, Jones DA, Degens H. Decrements of mobility and && dietary protein needs and influences on skeletal muscle of older adults. J
power in recreationally active septuagenarians is related to loss of force, but Gerontol and Biol Sci Med Sci 2023; 78(Suppl 1):67–72.
not slowing of the muscle: a 5-year longitudinal study. Eur J Appl Physiol A complete review covering the metabolic and clinical aspects of optimal nutri-
2023; 123:1369–1379. tional support of older adults.
11. Teraž K, Marusic U, Kalc M, et al. Sarcopenia parameters in active older adults 35. Chang MC, Choo YJ. Effects of whey protein, leucine, and vitamin D
– an eight-year longitudinal study. BMC Public Health 2023; 23:917. & supplementation in patients with sarcopenia: a systematic review and
12. Mayhew AJ, Amog K, Phillips S, Parise G. The prevalence of sarcopenia in meta-analysis. Nutrients 2023; 15:521.
community-dwelling older adults, an exploration of differences between A complete review and meta-analysis of effects of whey protein, leucine, and
studies and within definitions: a systematic review and meta-analyses. Age vitamin D supplementation in patients with sarcopenia.
Ageing 2019; 48:48–56. 36. Kwon HE, Ko N, Yuk D, et al. Improved muscle mass and function with protein
13. Moroni A, Perna S, Azzolino D, et al. Discovering the individualized factors & supplementation in older adults with sarcopenia: a meta-analysis. Ann Rehabil
associated with sarcopenia and sarcopenic obesity phenotypes – a machine Med 2023; 47:358–366.
learning approach. Nutrients 2023; 15:4536. An excellent meta-analysis of muscle mass and function with protein supplementa-
14. Petermann-Rocha F, Balntzi V, Gray SR, et al. Global prevalence of sarco- tion in older adults with sarcopenia.
& penia and severe sarcopenia: a systematic review and meta-analysis. J 37. Guo Y, Fu X, Hu Q, et al. The effect of leucine supplementation on sarcopenia-
Cachexia Sarcopenia Muscle 2022; 13:86–99. & related measures in older adults: a systematic review and meta-analysis of 17
A comprehensive review to estimate the global and region-specific prevalence of randomized controlled trials. Front Nutr 2022; 9:929891.
sarcopenia and severe sarcopenia by sociodemographic factors. A meta-analysis of the randomized controlled trials on leucine supplementation in
15. Granic A, Suetterlin K, Shavlakadze T, et al. Hallmarks of ageing in human sarcopenic patients.
&& skeletal muscle and implications for understanding the pathophysiology of 38. Izquierdo M, Merchant RA, Morley JE, et al. International exercise. recom-
sarcopenia in women and men. Clin Sci (Lond) 2023; 137:1721–1751. mendations in older adults (ICFSR): expert consensus guidelines. J Nutr
An updated and complete review of the pathophysiology of sarcopenia in women Health Aging 2021; 25:824–853.
and men and of the clinical implications. 39. Kelley GA, Kelley KS, Stauffer BL. Effects of resistance training on body
16. Coletti C, Acosta GF, Keslacy S, Coletti D. Exercise-mediated reinnervation of weight and body composition in older adults: An inter-individual response
skeletal muscle in elderly people: an update. Eur J Transl Myol 2022; 32:10416. difference meta-analysis of randomized controlled trials. Sci Prog 2023;
17. Ladang A, Beaudart C, Reginster JY, et al. Biochemical markers of muscu- 106:368504231179062.
loskeletal health and aging to be assessed in clinical trials of drugs aiming at 40. Hurst C, Robinson SM, Witham MD, et al. Resistance exercise as a treatment
the treatment of sarcopenia: consensus paper from an Expert Group Meeting for sarcopenia: prescription and delivery. Age Ageing 2022; 51:afac003.
Organized by the European Society for Clinical and Economic Aspects of 41. Shen Y, Shi Q, Nong KLi, et al. Exercise for sarcopenia in older people: a
Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) and & systematic review and network meta-analysis. J Cachexia Sarcopenia Muscle
the Centre Acad
emique de Recherche et d’Exp
erimentation en Sant
e 2023; 14:1199–1211.
(CARES SPRL), Under the Auspices of the World Health Organization An updated review on the potential of exercise in sarcopenic older people.
Collaborating Center for the Epidemiology of Musculoskeletal Conditions 42. Goh J, Wong E, Soh J, et al. Targeting the molecular and cellular pillars of
and Aging. Calcif Tissue Int 2023; 112:197–217. human aging with exercise. FEBS J 2023; 290:649–668.
18. Moiseeva V, Cisneros A, Sica V, et al. P. Senescence atlas reveals an aged- 43. O’Bryan SJ, Hiam D. The benefits of physical activity on neuromuscular
like inflamed niche that blunts muscle regeneration. Nature 2023; structure and function in old age. J Physiol 2022; 600:2283–2285.
613:169–178. 44. Nunes EA, Colenso-Semple L, McKellar SR, et al. Systematic review and
19. Park SY, Hwang BO, Song NY. The role of myokines in cancer: crosstalk & meta-analysis of protein intake to support muscle mass and function in healthy
& between skeletal muscle and tumor. BMB Rep 2023; 56:365–373. adults. J Cachexia Sarcopenia Muscle 2022; 13:795–810.
A synthetic updated review concerning an integrative understanding of crosstalk An authoritative review of the relationship between protein intake and muscle mass
between skeletal muscle and tumour with potential clinical implications. and function in healthy adults.

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MCO 270501

Age-related and cancer-related sarcopenia: is there a difference? Bozzetti

45. Li M, Chi X, Wang Y, et al. Trends in insulin resistance: insights into mechanisms 68. Wilson TN, Roquelaure Y, Evanoff B, et al. Physical activity in
and therapeutic strategy. Signal Transduct Target Ther 2022; 7:216S. people diagnosed with cancer: a rapid review of recommendations and
46. Kuang J, McGinley C, Lee MJ-C, et al. Interpretation of exercise-induced critical appraisal of international guidelines. Support Care Cancer 2023;
changes in human skeletal muscle MRNA expression depends on the timing 31:679.
of the post-exercise biopsies. Peer J 2022; 10:e12856. 69. Johal J, Han CY, Joseph R, et al. Dietary supplements in people with
47. Krakov
a D, Holwerda AM, Betz MW, et al. Muscle fiber type grouping does not metastatic cancer who are experiencing malnutrition, cachexia, sarcopenia,
change in response to prolonged resistance exercise training in healthy older and frailty: a scoping review. Nutrients 2022; 14:2642.
men. Exp Gerontol 2023; 173:112083. 70. Klassen P, Schiessel DL, Baracos VE. Adverse effects of systemic cancer
48. Park S, Park SK, Jee YS. Moderate- to fast-walking improves immunocytes && therapy on skeletal muscle mass: myotoxicity comes out of the closet. Curr
through a positive change of muscle contractility in old women: a pilot study. J Opin Clin Nutr Metab Care 2023; 26:210–218.
Exerc Rehabil 2023; 19:45–56. A complete and updated review of the adverse effects of systemic cancer therapy
49. Gharahdaghi N, Rudrappa S, Brook MS, et al. Pharmacological hypogonad-
Ho4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 03/18/2024
Downloaded from http://journals.lww.com/co-clinicalnutrition by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsI

on skeletal muscle mass.

ism impairs molecular transducers of exercise-induced muscle growth in 71. Klassen PN, Mazurak VC, Thorlakson J, Servais S. Call for standardization in
humans. J Cachexia Sarcopenia Muscle 2022; 13:1134–1150. & assessment and reporting of muscle and adipose change using computed
50. Song Z, Pan T, Tong X, Yang Y, et al. The effects of nutritional supplementa- tomography analysis in oncology: a scoping review. J Cachexia Sarcopenia
& tion on older sarcopenic individuals who engage in resistance training: a meta- Muscle 2023; 14:1918–1931.
analysis. Front Nutr 2023; 10:1109789. A punctual analysis of the critical issues related to define sarcopenia.
An updated meta-analysis on the effects of resistance training in older sarcopenic 72. Wang P, Wang S, Li X, et al. Skeletal muscle wasting during neoadjuvant
patients. therapy as a prognosticator in patients with esophageal and esophagogastric
51. Cereda E, Pisati R, Rondanelli M, Caccialanza R. Whey protein, leucine- and junction cancer: a systematic review and meta-analysis. Int J Surg 2022;
& vitamin-D-enriched oral nutritional supplementation for the treatment of sar- 97:106206.
copenia. Nutrients 2022; 14:1524. 73. Klassen PN, Baracos V, Ghosh S, et al. Muscle and adipose wasting despite
A critical analysis on the effects of whey protein, leucine- and vitamin-D-enriched disease control: unaddressed side effects of palliative chemotherapy for
oral nutritional supplementation in sarcopenic subjects. pancreatic cancer. Cancers 2023; 15:4368.
52. Lee SY, Lee HJ, Lim JY. Effects of leucine-rich protein supplements in older 74. Mallard J, Hucteau E, Charles A-L, et al. Chemotherapy impairs skeletal
& adults with sarcopenia: a systematic review and meta-analysis of randomized muscle mitochondrial homeostasis in early breast cancer patients. J Cachexia
controlled trials. Arch Gerontol Geriatr 2022; 102:104758. Sarcopenia Muscle 2022; 13:1896–1907.
An update on the role of leucine. 75. VanderVeen BN, Cardaci TD, Madero SS, et al. 5-Fluorouracil disrupts
53. Martin A, Gallot YS, Freyssenet D. Molecular mechanisms of cancer cachexia- skeletal muscle immune cells and impairs skeletal muscle repair and remodel-
related loss of skeletal muscle mass: data analysis from preclinical and clinical ling. J Appl Physiol 2022; 133:834–849.
studies. J Cachexia Sarcopenia Muscle 2023; 14:1150–1167. 76. Huot JR, Pin F, Chatterjee R, Bonetto A. PGC1a overexpression preserves
54. Kim HG, Huot JR, Pin F, et al. Reduced rDNA transcription diminishes skeletal muscle mass and function in cisplatin-induced cachexia. J Cachexia Sarco-
muscle ribosomal capacity and protein synthesis in cancer cachexia. FASEB J penia Muscle 2022; 13:2480–2491.
2021; 35:e21335. 77. Ikeno Y, Inomata M, Tsukimura Y, et al. Eicosapentaenoic acid suppresses
55. Kadakia KC, Hamilton-Reeves JM, Baracos VE. Current therapeutic targets in cisplatin-induced muscle atrophy by attenuating the up-regulated gene ex-
&& cancer cachexia: a pathophysiologic approach. Am Soc Clin Oncol Educ pression of ubiquitin. J Nutr Biochem 2022; 103:108953.
Book 2023; 43:e389942. 78. Liu X, Xu M, Yu Y, et al. PD-1 alleviates cisplatin-induced muscle atrophy by
This article reviews the major thematic areas that are driving pharmacologic strate- regulating inflammation and oxidative stress. Antioxidants (Basel) 2022;
gies, including those targeting signal mediators at the level of the CNS and skeletal 11:1839.
muscle in cancer cachexia. Furthermore, it highlights recently published and ongoing 79. Matsumoto C, Sekine H, Nahata M, et al. Role of mitochondrial dysfunction in
trials evaluating cancer cachexia therapies in these specific areas. the pathogenesis of cisplatin-induced myotube atrophy. Biol Pharm Bull
56. Talbert EE, Guttridge DC. Emerging signaling mediators in the anorexia- 2022; 45:780–792.
cachexia syndrome of cancer. Trends Cancer 2022; 8:397–403. 80. Sakai H, Zhou Y, Miyauchi Y, et al. Increased 20S proteasome expression and
57. Zhong X, Narasimhan A, Silverman LM, et al. Sex specificity of pancreatic the effect of bortezomib during cisplatin-induced muscle atrophy. Biol Pharm
cancer cachexia phenotypes, mechanisms, and treatment in mice and hu- Bull 2022; 45:910–918.
mans: role of activin. J Cachexia-Sarcopenia Muscle 2022; 13:2146–2152. 81. VanderVeen BN, Cardaci TD, Madero SS, McDonald SJ. 5-Fluorouracil
58. Yan W, Cao M, Ruan X, Jiang L, et al. Cancer-cell-secreted miR-122 disrupts skeletal muscle immune cells and impairs skeletal muscle repair
suppresses O-GlcNAcylation to promote skeletal muscle proteolysis. Nat and remodeling. J Appl Physiol 2022; 133:834–849.
Cell Biol 2022; 24:793–804. 82. Mallard J, Hucteau E, Bender L, et al. Development of skeletal muscle
59. Hu Y, Liu L, Chen Y, Zhang X, et al. Cancer-cell-secreted miR-204-5p induces atrophy and intermuscular adipose tissue in patients with early breast cancer
leptin signalling pathway in white adipose tissue to promote cancer-asso- treated with chemotherapy. Am J Physiol Cell Physiol 2022; 323:
ciated cachexia. Nat Commun 2023; 14:5179. C1325–C1332.
60. Casariego AV, García Luna PP, Luna, et al. Impact of an oral nutritional 83. Mallard J, Hucteau E, Charles AL, et al. Chemotherapy impairs skeletal muscle
supplement enriched in leucine, EPA, DHA, and b-glucans on the increase of mitochondrial homeostasis in early breast cancer patients. J Cachexia Sar-
muscle mass in patients with cancer and malnutrition: the Alisenoc trial. J copenia Muscle 2022; 13:1896–1907.
Funct Foods 2023; 110:105833. 84. Amitani M, Oba T, Kiyosawa N, et al. Skeletal muscle loss during neoadjuvant
61. Mavropalias G, Sim M, Taaffe DR, et al. Exercise medicine for cancer chemotherapy predicts poor prognosis in patients with breast cancer. BMC
cachexia: targeted exercise to counteract mechanisms and treatment side Cancer 2022; 22:327.
effects. J Cancer Res Clin Oncol 2022; 148:1389–1406. 85. Jang MK, Park S, Park C, et al. Body composition change during neoadjuvant
62. Clemente-Su
arez VJ, Redondo-Flórez L, Rubio-Zarapuz A, et al. Nutritional chemotherapy for breast cancer. Front Oncol 2022; 12:941496.
and exercise interventions in cancer-related cachexia: an extensive narrative 86. Jang MK, Park S, Park C, et al. Does neoadjuvant chemotherapy regimen
review. Int J Environ Res Public Health 2022; 19:4604. affect sarcopenia status in patients with breast cancer? Breast 2022;
63. Schauer T, Mazzoni A-S, Henriksson A, Demmelmaie I. Exercise intensity and 66:1–7.
markers of inflammation during and after (neo-) adjuvant cancer treatment. 87. Ikeda T, Noma K, Maeda N, et al. Effectiveness of early exercise on reducing
Endocr Relat Cancer 2021; 28:191–201. skeletal muscle loss during preoperative neoadjuvant chemotherapy for
64. Papadopetraki A, Giannopoulos A, Maridaki M, et al. The role of exercise in esophageal cancer. Surg Today 2022; 52:1143–1152.
cancer-related sarcopenia and sarcopenic obesity. Cancers 2023; 15:5856. 88. Allen SK, Brown V, White D, et al. Multimodal prehabilitation during neoad-
65. Torregrosa C, Chorin F, Beltran EEM, et al. Physical activity as the best juvant therapy prior to esophagogastric cancer resection: effect on cardio-
supportive care in cancer: the clinician’s and the researcher’s perspectives. pulmonary exercise test performance, muscle mass and quality of life-a pilot
Cancers (Basel) 2022; 14:5402. randomized clinical trial. Ann Surg Oncol 2022; 29:1839.
66. Mangano GD, Fouani M, D’Amico D, et al. Cancer-related cachexia: the 89. Della Peruta C, Lozanoska-Ochser B, Renzini A, Moresi V. Sex differences in
vicious circle between inflammatory cytokines, skeletal muscle, lipid meta- & inflammation and muscle wasting in aging and disease. Int J Mol Sci 2023;
bolism and the possible role of physical training. Int J Mol Sci 2022; 23:3004. 24:4651.
67. Bordignon C, Dos Santos BS, Rosa DD. Impact of cancer cachexia on cardiac A critical appraisal of the relationship among inflammation, sarcopenia and muscle
and skeletal muscle: role of exercise training. Cancers (Basel) 2022; 14:342. wasting in men and women.

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