Journal of Orthopaedic Translation 23 (2020) 38–52

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Journal of Orthopaedic Translation

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Review Article

Sarcopenia: Current treatments and new regenerative

therapeutic approaches
Jessica Hiu-tung Lo a, b, ☆, Kin Pong U a, b, ☆, Tszlam Yiu a, b, Michael Tim-yun Ong a, **,
Wayne Yuk-wai Lee a, b, *
a
Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, PR China
b
Stem Cells and Regenerative Medicine Laboratory, Lui Che Woo Institute of Innovative Medicine, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong
Kong, Prince of Wales Hospital, Shatin, Hong Kong, PR China

A R T I C L E I N F O A B S T R A C T

Keywords: Sarcopenia is characterized by loss of muscle and reduction in muscle strength that contributes to higher mortality
Clinical trial rate and increased incidence of fall and hospitalization in the elderly. Mitochondria dysfunction and age-
Exercise associated inflammation in muscle are two of the main attributors to sarcopenia progression. Recent clinical
Inflammation
trials on sarcopenia therapies such as physical exercise, nutraceutical, and pharmaceutical interventions have
Mesenchymal stem/stromal cells
revealed that exercise is the only effective strategy shown to alleviate sarcopenia. Unlike nutraceutical and
Mitochondria
Sarcopenia pharmaceutical interventions that showed controversial results in sarcopenia alleviation, exercise was found to
restore mitochondria homeostasis and dampen inflammatory responses via a complex exchange of myokines and
osteokines signalling between muscle and bone. However, as exercise have limited benefit to immobile patients,
the use of stem cells and their secretome are being suggested to be novel therapeutics that can be catered to a
larger patient population owing to their mitochondria restoration effects and immune modulatory abilities. As
such, we reviewed the potential pros and cons associated with various stem cell types/secretome in sarcopenia
treatment and the regulatory and production barriers that need to be overcome to translate such novel therapeutic
agents into bedside application.
Translational potential: This review summarizes the causes underlying sarcopenia from the perspective of
mitochondria dysfunction and age-associated inflammation, and the progress of clinical trials for the treatment of
sarcopenia. We also propose therapeutic potential of stem cell therapy and bioactive secretome for sarcopenia.

Introduction- sarcopenia definition and aetiology of age [2]. This loss in muscle mass and consequently its strength results
in sarcopenia, a term that describes a prevalent age-associated decline
According to the United Nation's World Population Ageing 2015 in muscle mass, strength, and function, first introduced by Irwin
report, the global number of people aged 60 years or above has Rosenberg [3]. Sarcopenia affects 10% (95% confidence interval [CI]:
increased substantially in recent years and is projected to accelerate in 8–12%) in men and 10% (95% CI: 8–13%) in women, respectively
the coming decades, doubling the number in 2015 by the year 2050 to [134]. Meta-analysis indicated that sarcopenia is associated with higher
an astonishing 2.1 billion people [1]. Ageing is a multifactorial process rate of mortality (pooled odds ratio [OR] of 3.596, 95% CI: 2.96–4.37),
that is associated with numerous changes in body composition including muscle functional decline (pooled OR of 3.03, 95% CI: 1.80–5.12),
bone mass, muscle mass, and adipose tissue composition. Muscle, being higher rate of falls and higher incidence of hospitalization [4]. Epide-
the largest organ in the body that makes up 40% of the body mass miological studies indicated that muscle ageing is associated with a
shows an apparent and progressive reduction in the size and number of number of degenerative disorders such as osteoporosis, type II diabetes,
muscle fibres (up to 30%) in an age-dependent way from 25 to 80 years and cancer [5,6].

* Corresponding author. Department of Orthopaedics and Traumatology, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of
Hong Kong, Shatin, SAR, Hong Kong, PR China. Fax: þ(852) 2637 7889.
** Corresponding author. Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, SAR, Hong Kong, PR China.
E-mail addresses: [email protected] (M.T.-y. Ong), [email protected] (W.Y.-w. Lee).
☆
Lo JH and U KP contribute equally in this work.

https://doi.org/10.1016/j.jot.2020.04.002
Received 12 December 2019; Received in revised form 31 March 2020; Accepted 2 April 2020
Available online 30 April 2020
2214-031X/© 2020 The Author(s). Published by Elsevier (Singapore) Pte Ltd on behalf of Chinese Speaking Orthopaedic Society. This is an open access article under
the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
J.H.-t. Lo et al. Journal of Orthopaedic Translation 23 (2020) 38–52

It is known that sarcopenia is a multifactorial condition with varying occur resulting in an increase in levels of apoptosis [16] and reduced
outcomes and can be observed in both older and younger adults, as is capabilities for muscle regeneration [17] that were commonly observed
likewise the case for dementia and osteoporosis, sarcopenia can be in sarcopenic patients [18]. In addition to the muscular changes,
clinically considered “primary” (or age-related) or “secondary” (when age-related mitochondria deregulation also results in motor neuronal cell
one or more other causes are evident) (Supplementary Table 1) [9]. death [19], that ultimately resulted in innervation impairment [20] and
Sarcopenia has been underdiagnosed in the past owing to the lack of an ~27% reduction in the motor unit pool that possibly accounts for the
consensus on clinical definition. The European Working Group on Sar- muscular atrophy [20,21] and loss in muscular contractile force in sar-
copenia in Older People defined specific clinical parameters for sarco- copenic aged humans and rodents [22].
penia based on low muscle mass and low muscle function. Thereafter, The mitochondria are double membrane bound organelles that
International Working Group on Sarcopenia published an US guideline in contain their own genetic material, the mitochondria DNA (mtDNA) and
2011, and Asian Working Group for Sarcopenia provided guidelines for produces ATP through the electron transport chain process which con-
Asian population in 2014 [7,8]. These guidelines (which have been sists of a series of oxphos reactions [23,24]. The oxphos reactions in
reviewed extensively elsewhere are not included in this review) with mitochondria produces high levels of ROS which are damaging for
ethnic-based modified parameters set the stage for further intensive mtDNA, creating mutations, and deletion in them [25,26]. Hence,
investigation on the etiopathogenesis and intervention. mitochondria fission and fusion are in place to maintain mitochondria
In accordance to the European Working Group on Sarcopenia in Older homeostasis in the cell [24]. Mitochondria fusion and fission are two
People, sarcopenia is further subgrouped based on the presence of both different processes with fusion being to process that mitigates stress by
low muscle mass, low muscle strength, and low physical performance, mixing contents of partially damaged mitochondria as a form of
which dependent on the results and characteristics, was further defined complementation while the latter being the process necessary to create
into conceptual stages as “presarcopenia”, “sarcopenia” and “severe new mitochondria and contribute to quality control of mitochondria via
sarcopenia” (Supplementary Table 2). “Presarcopenia” stage is charac- removal of damaged mitochondria [27].
terized by low muscle mass in reference to standard population. The However, as age progresses, mitochondria homeostasis is no longer
“sarcopenia” is characterized by concurrent reduction in muscle strength maintained due to numerous processes, namely the building up of ROS
or physical performance in addition to low muscle mass. “Severe sarco- [28] which can be attributed to the reduction in antioxidant enzyme
penia” is defined when all three diagnostic criteria met including low levels in both muscle and neuron cells [29] (Fig. 1). This accumulation of
muscle mass, strength and low physical performance. Recognizing stages ROS results in mtDNA deletion or mutation causing mitochondrial
of sarcopenia may help in selecting treatments and setting appropriate dysfunction [30,31]. To further add on to the already dire situation,
recovery goals. Staging may also support design of research studies that mitophagy–proteosome–induced mitochondria clearance function also
focus on a particular stage or on-stage changes over time. However, deteriorates with age [17,32]. As the number of damaged mitochondria
staging of sarcopenia can be complicated by other medical conditions accumulates, not only does the mitochondria not able to produce suffi-
that are associated with prominent muscle wasting such as cachexia, cient ATP to sustain cellular function in muscle and neurons, there will
frailty, and sarcopenic obesity. As such, it is important to distinguish such also not be enough normal functional mitochondria to act as comple-
medical conditions from age-related sarcopenia to guide targeted and mentary partners for mitochondria fusion to take place to restore mito-
appropriate therapy for each sarcopenia type [9]. chondria homeostasis. These events ultimately lead to damaged
Though the biological mechanism underlying sarcopenia is not mitochondria membrane potential and leakage of mitochondria content
clearly understood [10], there is a growing scientific and public interest to the cell cytosol that initiates apoptosis in both muscle and neurons,
to develop effective approaches to counteract the effects of sarcopenia to leading to muscular atrophy and muscle dennervation in sarcopenia (Fig.
maintain functional independence or known as “active ageing”. In this 2) [27].
review, we summarize the definition and consequences of sarcopenia,
reviewed how ageing-associated factors, including mitochondria and Inflammation in sarcopenia
energy homeostasis dysfunction [11,12], reactive oxygen species (ROS)
accumulation [13,14] and inflammation [15] play important roles in the In normal physiological conditions, the immune system plays an
aetiology of age-related sarcopenia. Secondly, we looked into the pros important role in protecting the body from pathogens. Inflammation is a
and cons of the currently available therapeutic options, including exer- response elicited by immune cells such as macrophages, dendritic cells,
cise, pharmaceutical and nutraceutical interventions, for sarcopenia with and Th cells in the event of infection to allow the body to clear off
focus on how exercise alleviates sarcopenia by targeting the mentioned pathogens from the body. However, as the body ages, hormonal changes
sarcopenia attributing factors and the therapeutic limitation associated such as decrement in testosterone, growth hormones, androgens, oes-
with physical exercise. Finally, we reviewed the potential therapeutic trogen occur, and this tips the balance of the body towards a state of
effects, pros and cons of administering stem cell and stem cell secretome chronic inflammation with increased plasma levels of proinflammatory
as novel therapeutic options for sarcopenia and the associated technical mediators, such as tumour necrosis factor α (TNF-α), interleukin 6 (IL-6),
and regulatory barriers that need to be overcome. and C-reactive protein (CRP) (Table 1) [33]. This chronic inflammation
status causes an increased number of cells to leave cell cycle, enter the
Causes of sarcopenia state of cellular senescence, and acquire a senescence-associated secre-
tory phenotype (SASP), further inducing the production of proin-
Mitochondria dysfunction and sarcopenia flammatory cytokines such as TNF-α, IL-6, and NF-κB [34,35] (Fig. 2).
The upregulation of inflammatory cytokines, particularly in the
Muscle, being the largest organ in the body, is mainly made up of microenvironment of muscle contributes to the upregulation of apoptosis
highly contractile and energy-dependent myocytes. To carry out its and senescence of myocytes (Fig. 2). Inflammatory cytokines such as IL-6
contractile function, muscle cells receive neurotransmitters such as and TNF-α mainly function as signalling molecules that recruit inflam-
acetylcholine and dopamine from motor neurons at the motor plates. It is matory cells into site of infection while concurrently enhance their
well established that both the muscle and neurons are high energy antipathogen clearance functions such as phagocytosis. However, in the
consuming cells which are greatly addicted to adenosine triphosphate ageing scenario, IL-6 and TNF-α recruit inflammatory cells to the muscle
(ATP) supply for them to function and are hence highly dependent on the and this initiates the vicious cycle of inducing cellular senescence, pro-
proper functioning of mitochondria, the powerhouse and ATP supply duction of SASP, further inflammatory cells recruitment and as a result
organelle of the cell. aged muscle will be overwhelmed by vast amount of inflammatory
As age takes toll, mitochondria dysfunction in the muscle started to cytokine, particularly TNF-α [36,37] (Fig. 2). TNF-α functions by binding

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J.H.-t. Lo et al. Journal of Orthopaedic Translation 23 (2020) 38–52

Figure 1. Factors contributing to ageing include mitochondrial fusion/fission failure, replicative senescence, unresponsive to changes in microenvironment, telomere
shortening, ROS accumulation and loss of antioxidants. Mitochondria fusion/fission failure gives rise to the gradual build up in mitochondria DNA mutation owing to
the inability of the cells to minimize the mutation ratio of mitochondria DNA via mitochondria fusion and the inability of the cells to produce new mitochondria to
replace the dysfunctional ones. With the build up of defective mitochondria, prolonged division of cells and the build up of ROS, cellular senescence take place that
ultimately results in stem cell depletion.

to receptors on cell surface, initiating the recruitment of adaptor proteins, nutritional intervention.
eventually resulting in a death-induced caspase cascade. This was
confirmed by previous findings by Dirks and Leeuwenburgh in 2002 that Therapeutic intervention for sarcopenia
indicated an elevation in apoptosis (þ50%) (measured by nucleosome
fragmentation) was observed in 24 months old rats compared with 6 Based on the current understanding on the possible underlying causes
months old young rats [38]. The same group has also reported the higher of sarcopenia that includes malnutrition, chronic inflammation and lack
susceptibility of aged type II muscle fibres to TNF-α stimulated apoptotic of exercises, several clinical trials have been conducted to evaluate the
signalling, partially attributing to the greater loss of fast twitch muscle feasibility and potential efficacy of using exercise, especially resistant
fibre with ageing, a phenotype frequently presented in sarcopenia pa- training, commercial nutraceuticals (amino acid, vitamins supplements
tients [39]. or mixed compounds), and drug for muscle mass and strength building. A
In addition to the apoptotic effects of inflammatory cytokines on literature search was performed to have a better understanding on the
myocytes, inflammatory cytokines also affect the muscle regeneration landscape of sarcopenia related clinical studies over the past ten years. In
capabilities [40]. Under normal conditions, satellite cells remain in a clinicaltrials.gov, a search with the keywords of “sarcopenia” AND
quiescent state. Upon muscle damage, satellite cells will regenerate “treatment” and inclusion criteria of “10 years” results in 23 registered
damaged muscle by re-entering into cell cycle [41]. However, as the trials including those with an “Unknown” and “Recruiting” status
muscle ages, the pool of Pax7 expressing satellite cells decrease resulting (Table 2). A PubMed clinical search with “sarcopenia AND intervention”
in the inability of satellite cells in aged muscle to drive the expression of showed 115 clinical trials (excluding 81 irrelevant reports) published
myogenic differentiation genes such as Myf5 and MyoD [42,43]. The over the past ten years. At the time of writing, a total of 34 relevant
decrement in Pax7 expressing satellite cells along with altered notch clinical trials were selected for reporting (Table 2). It appears that ex-
signalling, deprivation of growth differentiation factor 11 (GDF11), Igf-1, ercise and nutraceuticals administration account for about 76% of main
and increased inflammation and proinflammatory cytokines in age treatment strategy for sarcopenia clinical trials; while drugs adminis-
muscle causes deterioration in satellite cell function(s) [44–46] (Fig. 2). tration such as testosterone and metformin and whole body electrical
As such, inflammation-mediated myocyte apoptosis and loss of satellite myostimulation (WB-EMS) were less frequently adopted therapeutic
cells’ muscle regenerating capabilities are few of the many sarcopenia approaches (Fig. 3). Of note, WB-EMS was the only studied physical
mediating factors that are targeted by numerous pharmaceutical com- stimulation for sarcopenia under the searching criteria. Whole body vi-
panies as potential candidates for therapeutic development in addition to bration is emerging as alternative physical intervention attracting

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Figure 2. Schematic diagram illustrating the microenvironmental and intracellular changes in young and old muscular microenvironment. (A) In the physiological
microenvironment of young individual, low level of inflammatory cytokines is present with highly abundant neural plates and low level of apoptotic and senescence
cells in the muscle. Pax 7 satellite cells are abundant and responsive to external stimulation such as physical activities and nutritional stimulation that facilitate muscle
building. The mitochondria within the muscle cells, neurons and satellite cells are intact and highly functional and efficient in energy (ATP) production. Proper
clearance of dysfunctional mitochondria and properly regulated mitochondria fusion and fission are in place to ensure mitochondria homeostasis in the cells. This
ensures cellular viability and function that are essential in muscular function and muscle building. (B) In the physiological microenvironment of aged/old individual,
dysfunction mitochondria are in high abundance owing to deregulated mitophagy–proteasome–induced mitochondria clearance and disruptive mitochondria fusion
and fission. This results in the accumulation of ROS the trigger cellular senescence in muscle cells, neurons and satellite cells. Senescent cells will release SASP that will
initiate an inflammatory cascade that causes more cells to undergo senescence and apoptosis that ultimately results in denervation of muscle and muscle loss in
sarcopenia. SASP, senescence-associated secretory phenotype.

researchers’ attention most recently [59] (https://clinicaltrials.gov/ct2/ effective intervention on sarcopenia alleviation. Of a total of 34 studies
show/NCT04028206). listed, only those involving physical activity interventions showed a
Based on the findings from the ongoing and/or completed clinical significant improvement in muscle strength and performance regardless
trials for sarcopenia training exercise is demonstrated to be the most of whether it is aerobic, anaerobic, or resistance type of exercise. On the

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Table 1
Pro-inflammatory cytokines change with ageing.
Cytokines Sample size (cohort/ethnic) Age (gender) Key findings Reference

TNF-α n ¼ 174 (1914 cohort in Glostrup) Aged: 81 years Plasma TNF-α in elderly 81 years is higher than [47]
Control: 19–31 years young adults 19–31 years
(M+F)
n ¼ 232 (The Danish Centenarian Aged: 100 years Plasma TNF-α in centenarian 100 years (3.7 pg/ml) [48]
Study) Control: 18–31 years is higher than young adults 18–30 years (1.4 pg/ml)
(M+F)
n ¼ 2944 30–79 years (F) Serum TNF-a in elderly 60–79 years (>9 pg/ml) is [49]
higher than young adults 30–59 years (7 pg/ml)
n ¼ 70 21–94 years (M+F) Significant correlation between age and TNFα [50]
(r ¼ 0.64)
n ¼ 56 20–80 years (M+F) Plasma TNF-α level in elderly 65–79 years is higher [51]
than young adults 20–33 years
n ¼ 2746 (The Health, Aging, and 70–79 years (M+F) Plasma TNF-α level is higher in white people in both [52]
Body Composition (Health ABC) Study women and men.
cohort/ Black: n ¼ 1132; White:
n ¼ 1614)
IL-6 n ¼ 62 26–75 years (M+F) Plasma IL-6 level in elderly 55–75 years [53]
(>5.67  2.02 pmol/l) is higher than young adults
26–54 years (>4.8  1.43 pmol/l)

n ¼ 1727 (The Duke component of the 65 years (M+F) Mean log plasma IL-6 level in elderly 70–79 years [54]
NIA-funded study of the Established (1.03 pg/ml) is higher than elderly 90–99 years
Populations for Epidemiologic Studies (1.23 pg/ml)
of the Elderly/Black: n ¼ 913; non-
Black: n ¼ 814)
n ¼ 675 (Healthy, nondisabled Mean age of 77.8  3.2 years (M+F) Log values of serum IL-6 level in elderly 71–72 years [55]
participants in the Iowa 65+ Rural (0.73  0.66 pg/ml) is higher than over 80 years
Health Study) (0.96  0.65 pg/ml)
n ¼ 1343 20–102 years (M+F) Serum IL-6 level in elderly over 75 years (>1.4 pg/ [56]
ml) is higher than young adults 20–39 years
(0.6 pg/ml)
n ¼ 2746 (The Health, Aging, and 70–79 years (M+F) Plasma IL-6 level is lower in white people in both [52]
Body Composition (Health ABC) Study women and men.
cohort/Black: n ¼ 1132; White:
n ¼ 1614)
n ¼ 63 Mean age of 71.2  7.4 years (F) Inverse correlation between IL-6 levels and manual [57]
muscle strength
CRP n ¼ 1343 20–102 years (M+F) Serum CRP level in elderly over 75 years (>2.6 g/l) [56]
is higher than young adults 20–39 years (1.0 g/l)
n ¼ 3632 65–69, 70–74, 75–79, 80–84, 85–89 Serum CRP level in elderly over 80 years (>2.4 mg/ [58]
and 90 years (M+F) l) is higher than elderly aged 65–69 years (2.2 mg/l)
n ¼ 2944 30–79 years (F) Serum Hs-CRP level in elderly 60–79 years [49]
(>1.1 mg/l) is higher than young adults 30–59
years (0.95 mg/l)

Table modified from [33]. IL-6, interleukin 6; HS-CRP, high sensitivity C-reactive protein; TNF-α, tumor necrosis factor α.

other hand, nutraceuticals and pharmaceutical interventions were not as inflammatory. In the immune system, there are cells which are proin-
effective nor did they show promising synergistic effect when adminis- flammatory, such as type I macrophage and T-helper cells [65,66], and
tered concurrently with exercise regime. anti-inflammatory cells such as type II macrophages and regulatory T
(Treg) cells [65,66]. In the aged body, where a proinflammatory
microenvironment is present, proinflammatory cells are mainly acti-
Physical exercise and sarcopenia vated, resulting in the production of TNF-α. In the case of exercised
muscle, the role of inflammatory cytokines such as IL-6 and chemotactic
Physical exercise regardless of it being aerobic or anaerobic, high or proteins such as monocyte chemotactic protein 1, fractalkine/CX3CL1
low resistance has been well accepted to be an important regime to function to recruit immune cells, and facilitate their migration and
prevent and treat not only chronic and degenerative diseases but also infiltration into the muscle [67], however, concurrently, the production
age-associated diseases such as cardiovascular diseases, cancer, neuro- of IL-10 and the IL-1 receptor antagonist switches the proinflammatory
degenerative diseases, psychiatric disorders, chronic pulmonary diseases, reaction to an anti-inflammatory reaction [68] which is reflected by the
diabetes, morbid obesity, and sarcopenia [60,61]. Muscle, being the decrease in systemic concentrations of several inflammatory cytokines
main player in both locomotion an endocrine secretion, it is not sur- which are associated with low-grade systemic inflammatory state such as
prising to see changes in secretory profile of muscles such as elevation in obesity and insulin resistance, cardiovascular diseases, atherosclerosis,
cytokines (IL-6, IL-8, IL-10, IL-15, CC-chemokine ligand 2 (CCL2), IL-1 and neurodegenerative disorders [69,70] (Fig. 4).
receptor antagonist, VEGF), angiopoietin-like 4 (ANGPTL4), Other than the anti-inflammatory effects of exercise, physical training
brain-derived neurotrophic factor, connective tissue growth factor, also significantly has improvements in the cardiovascular aspects, such as
cysteine-rich angiogenic protein 61, fractalkine and nicotinamide phos- increased cardiac output and enhanced blood volume. One of the most
phoribosyl transferase upon exercise or physical training [62–64]. important angiogenic factor produced by skeletal muscle upon physical
As mentioned, inflammation, nutritional deprivation, and mito- training is vascular endothelial growth factor (VEGF) [71]. Yet, there is
chondrial dysfunction are well-known factors contributing to sarcopenia no evidence suggesting an altered VEGF level after training, indicating
progression. The production of exercise-induced cytokines in muscle tips that VEGF increment and its effects are mainly localized to the muscles
the inflammatory microenvironment of the aged body towards anti-

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Table 2
List of sarcopenia clinical trials using nutraceuticals, protein supplements and exercise as therapeutic interventions individually or concurrently.
Year Sample Age Treatment Cotreatment Treatment Control groups Longest Assessment Reference
size/ (mean or method follow-
gender average) up time
point

2013 170/ Aged Drug Vitamin D and MK-0773 50 mg twice daily Placebo 6-month DXA, muscle strength [79]
Women 65 protein power,
supplementation physical performance
measures.
2015 380/All Aged Nutritional Vitamin D and leucine- Isocaloric 13-week Handgrip strength, [80]
65 supplement enriched whey protein control product SPPB score, chair-stand
nutritional supplement twice twice daily test,
daily gait speed,
balance score,
appendicular muscle
mass (by DXA)
2016 330/All Aged Nutritional Contained other Experimental ONS (E ONS, Control ONS (C 24-week Isokinetic peak torque [81]
65 supplement vitamins, minerals, 20 g protein; 499 IU vitamin ONS, 14 g leg strength, grip
and nutrients in D 3; 1.5 g CaHMB) taken protein; 147 IU strength,
varying amounts twice daily vitamin D 3) gait speed (m⋅s 1),
Left and right leg
muscle mass (by DXA),
Muscle quality (MQ)
was leg strength
expressed relative to
the tested LMM
2017 100/ Aged Physiological WB-EMS and protein Non- 16-week Sarcopenia Z-Score, [82]
Men 70 intervention supplementation (WB- intervention body fat rate (%),
and EMS&P) control skeletal muscle mass
Nutritional Isolated protein index,
supplement supplementation handgrip strength
2017 46/ Aged Exercise EG underwent elastic RET No RET 12-week Body composition (by [83]
Women 67.3 Each exercise session intervention DXA),
involved a general warm-up muscle quality defined
of 10 min, followed by as a ratio of muscular
resistance training exercises strength to muscle
(35–40 min), and finally a mass,
cool-down routine physical capacity
assessed using
functional mobility
tests
2018 110/All Mean Exercise Education including IC group consisted of 3-month Fat-free mass, muscle [84]
age 73.8 home-based exercise different modalities of strength,
exercise physical performance

LEE group performed

machine-based low
extremities exercise
2014 76/ Mean Physiological WB-EMS group (WB-EMS, Semi-active 54-week Body composition (by [85]
Women age 75 intervention n ¼ 38) that performed control group DXA), maximum
18 min of WB-EMS (bipolar, strength
85 Hz) 3 sessions in 14 days
(1.5 sessions/week)
2017 35/ Aged Exercise Study group underwent A 40-min 12-week DXA [86]
Women 60 progressive elastic band lesson about
resistance training for 12 the exercise
weeks (3 times per week) concept
2015 60/Men Aged Exercise and Guided training Collagen peptide silica 3-month Change in FFM Fat-free [87]
65 Nutritional programme on supplementation (15 g/d) mass,
supplement fitness devices (pull Body composition (by
down, leg press, DXA),
bench press, back Muscular strength (by
press, etc.) involving measuring isokinetic
all larger muscle quadriceps strength)
groups
2017 46/All Aged Nutritional Phytochemical compound Control (CON) 6-week Body composition (by [88]
61–77 supplement Protandim® (LifeVantage) at group DXA)
years the commercially available consumed
dose (one pill/day) placebo pills
Conjugated linoleic acid (high oleic
(CLA; 4 g/day) sunflower oil;
4 g/day)
2015 60/All Aged Nutritional n-3 PUFA consume 2 pills in Placebo control 6-month Thigh muscle volume, [89]
60–85 supplement the morning with breakfast (4 identical handgrip strength,
years and 2 pills in the evening looking pills/ one-repetition
with dinner d that maximum (1-RM)
(continued on next page)

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Table 2 (continued )
Year Sample Age Treatment Cotreatment Treatment Control groups Longest Assessment Reference
size/ (mean or method follow-
gender average) up time
point

contained corn lower- and upper-body

oil) strength,
average power during
isokinetic leg exercises
2016 30/ Aged Exercise Practice sessions for Two training groups no training 12-week MRI-measured muscle [90]
Women 61–86 the maximum performed bilateral squat (Ctrl, n ¼ 10) cross-sectional area
years voluntary isometric and knee extension exercise groups (CSA) at mid-thigh,
contraction (MVIC) training 2 days/week for 12 maximum voluntary
and knee extension weeks isometric contraction
and leg press 1RM The MH-Tr group exercised (MVIC) of knee
test at two exercise intensities extension, central
ranging from 5.6 to 8.4 on systolic blood pressure
the OMNI perceived exertion (c-SBP), central-
scale for resistance exercise augmentation index (c-
(OMNI-RES) for active AIx), cardio-ankle
muscle scale (0-extremely vascular index testing
easy to 10-extremely hard) (CAVI), ankle-brachial
which has been noted to pressure index (ABI).
correspond to exercise
intensity levels ranging from
approximately 70%–90% of
1RM for women
The BFR-Tr group used one
gold band for squatting, and
one black (Special Heavy)
band for knee extension. The
gold band was
approximately twice the
resistance level as the black
band, thus the two exercises
for the BFR-Tr group were
one-half (low-intensity level)
the intensity as that for the
MH-Tr group
2018 99/Men Aged Drug Receive 10 g of a transdermal Placebo 6-month mMscle strength and [91]
65 gel (100 mg of testosterone) physical function
(assessed by loaded
stair-climbing power)
2017 91/All Aged Drug 3  500 mg metformin Placebo group 16-week Handgrip strength, gait [92]
60 (every 4 weeks) speed, myostatin serum
level, and health-
related quality of life
(HR-QoL)
2015 64/All Aged Nutritional Creatine before (CR-B: Placebo (PLA: 32-week Body composition (by [93]
50–71 supplement n ¼ 15; creatine (0.1 g/kg) n ¼ 12; placebo DXA),
years immediately before immediately muscle strength (1-
resistance training and before and repetition maximum leg
placebo (0.1 g/kg cornstarch immediately press and chest press)
maltodextrin) immediately after resistance
after resistance training), training)
creatine after (CR-A: n ¼ 12;
placebo immediately before
resistance training and
creatine immediately after
resistance training)
2015 79/All Mean Nutritional Patients received The nutritional Controls 12- Body composition (by [94]
age 73.8 supplement calcium 1 g and supplementation group (group C, month DXA), handgrip
vitamin D 800 IE; (protein þ energy ¼ N n ¼ 25) strength (HGS) and
specifically, group) received a 200 ml received health-related quality
cholecalciferol package twice daily, each calcium 1 g and of life
(Calcichew-D3®; containing 20 g of protein vitamin D3 800
Takeda and 300 kcal (Fresubin®, IU daily
Pharmaceutical Fresenius Kabi, Bad
Company Limited, Homburg, Germany). This
Osaka, Japan) supplement was given for the
first six months following hip
fracture and was combined
with risedronate (Optinate®
Septimum; Sanofi AB,
Warner Chilcott,
Weiterstadt, Germany),
35 mg once weekly for 12
months
(continued on next page)

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Table 2 (continued )
Year Sample Age Treatment Cotreatment Treatment Control groups Longest Assessment Reference
size/ (mean or method follow-
gender average) up time
point

The second group (B)

received risedronate alone,
35 mg once weekly for 12
months
2017 50/All Mean Nutritional Participated in Long-chain n-3 PUFA Placebo 18-week Muscle size, strength, [95]
age 70.6 supplement lower-limb (n ¼ 23; 3 g fish oil/d) (n ¼ 27; 3 g and quality (strength
resistance exercise safflower oil/ per unit muscle area),
training twice d) functional abilities, and
weekly circulating metabolic
and inflammatory
markers
2016 15/Men Aged 62- Drug Progressive COX inhibitor Placebo (n ¼ 8; 12-week Muscle samples were [96]
66 resistance exercise (acetaminophen, 4 g/day; 64  2 years) examined for Type I
training program of n ¼ 7; 64  1 years) and II fibre cross-
bilateral knee sectional area,
extension that was capillarization, and
designed to metabolic enzyme
hypertrophy and activities (glycogen
strengthen the m. phosphorylase, citrate
quadriceps femoris synthase,
β-hydroxyacyl-CoA-
dehydrogenase)
2018 54/All Mean Exercise and Elastic band resistance Control group 6-month Skeletal muscle mass [97]
age 82.4 Nutritional training (N. ¼ 16) (N. ¼ 17) (by DXA), , isokinetic
supplement nutritional supplementation knee extension and
(N. ¼ 21) flexion force and
handgrip strength
2016 20/Men Aged Exercise Ingest 30 g protein from a 1 day Blood and muscle [98]
55–75 soy-dairy PB (n ¼ 9) or WPI amino acid
years beverage (n ¼ 10) at 1 h post- concentrations and
RE basal and postexercise
muscle protein turnover
2014 100/All Aged Nutritional 210 g of ricotta cheese (IG/ Control group 12-week Appendicular skeletal [99]
60 supplement HD þ RCH) was instructed muscle mass (by DXA),
to consume handgrip strength by a
only their handheld
habitual diet dynamometer, and
(CG/HD) physical performance
using the short physical
performance battery
(SPPB) and the stair-
climb power test
(SCPT)
2013 54/All Aged Nutritional Phase I consisted of two non- 24-week Strength and [100]
65 supplement exercise groups: (a) placebo functionality were
and (b) 3 g CaHMB assessed in both phases
consumed twice daily. Phase with isokinetic leg
II consisted of two resistance extension and flexion at
exercise groups: (a) placebo 60 ⋅s(-1) and 180 ⋅s(-1)
and resistance exercise and (LE60, LF60, LE180,
(b) 3 g CaHMB consumed LF180), hand grip
twice daily and resistance strength (HG) and get-
exercise (RE) up-and-go (GUG). DXA
was used to measure
arm, leg, and total body
lean mass (LM) as well
as total fat mass (FM).
Muscle Quality was
measured for arm
(MQ(HG) ¼ HG/arm
LM) and Leg
(MQ60 ¼ LE60/leg LM)
(MQ180 ¼ LE180/leg
LM).
2017 57/ Aged Exercise and Consumed 0.33 g/kg Engaged in a PRT Consumed 12-week DXA, maximal [101]
Women 50–70 Nutritional body mass of a milk- intervention (PRO þ PRT) 0.33 g/kg body voluntary isometric
years supplement based protein matrix mass of a milk- contraction, maximal
(PRO) based protein 900 m effort
matrix (PRO)
2013 46/ Mean Physiological WB-EMS group (n ¼ 23) “Active” 12- Whole-body and [102]
Women age 75 intervention which performed 18 min of control group month regional body
intermittent, bipolar WB- (n ¼ 23) composition was
assessed (by DXA) to
(continued on next page)

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J.H.-t. Lo et al. Journal of Orthopaedic Translation 23 (2020) 38–52

Table 2 (continued )
Year Sample Age Treatment Cotreatment Treatment Control groups Longest Assessment Reference
size/ (mean or method follow-
gender average) up time
point

EMS (85 Hz) three sessions in determine appendicular

14 days muscle mass, upper leg
muscle mass,
abdominal fat mass,
and upper leg fat mass.
Maximum strength of
the leg extensors was
determined
isometrically by force
plates.
2015 52/All Mean Exercise 16 weeks of progressive high 16-week Neuromuscular [103]
age 78 velocity resistance training activation was assessed
performed at low external using surface
resistance (40% of the 1- electromyography and
repetition maximum [1-RM] muscle cross-sectional
[LO]) area (CSA) was
high external resistance measured using
(70% of 1RM [HI]) computed tomography.
2013 80/All Aged 70- Nutritional Completed a Receive WPC (40 g/day) Isocaloric 6-month Change in whole-body [104]
85 supplement progressive high- control lean
intensity RT Muscle cross-sectional
intervention area, muscle strength
increased, Stair-
climbing performance
2016 91/ Mean Exercise Intervention groups (RT, 6-month Circulating levels of [105]
Women age 83.6 resistance training; RTS, myostatin, activin A,
resistance training plus follistatin, IGF-1 and
nutritional supplementation; GDF-15, as well as MQ
CT, cognitive training) and functional
parameters
2015 19/All Aged 61- Drug Continuous T (WK, n ¼ 5; Placebo (n ¼ 7) 5-month Muscle biopsies slow [106]
71 100 mg T enanthate, im and fast fibres included
injection) fibre diameter, peak
monthly cycled T (MO, n ¼ 7; force (P0), rate of
alternating months of T and tension development,
placebo) maximal shortening
velocity, peak power,
and Ca(2þ) sensitivity.
2009 81/All Aged 65- Exercise A 10-week unilateral Phase 1 ST Phase 2 ST Nonexercise 22-week Body composition [107]
85 ST program using Warm-up Warm-up control group Mid-Thigh
the untrained leg as set: 5 set: 5 Subcutaneous Fat,
an internal control repetitions repetitions Intermuscular Fat, and
preceded 12 weeks at 50% of at 50% of Muscle Volume of the
of whole-body ST 1RM 1RM Knee Extensors
30 s rest 30 s rest Muscle strength
Set 2: 15 Set 2: 5 Muscle power
repetitions repetitions Muscle Power
at 5RM* at 5RM
90 s rest
Set 3: 10
repetitions
at 5RM*
150 s rest
Set 4: 15
repetitions
at 5RM*
180 s rest
Set 5: 20
repetitions
at 5RM*

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J.H.-t. Lo et al. Journal of Orthopaedic Translation 23 (2020) 38–52

10
8
6
4
2
0
2009 2010 2013 2014 2015 2016 2017 2018

Exercise Nutritional supplement

Physiological intervention Drug

Drug
Physiological 15%
intervention
9%

Nutritional Exercise
supplement 38%
38%
Drug Exercise
Nutritional supplement Physiological intervention
Figure 3. A) Comparison of a number of clinical trials on sarcopenia interventions in accordance with a year of development. Each colour-coded part of the bar depicts
the corresponding interventions by year. (B) Percentage of treatments developed relative to the total number of studies.

[72] (Fig. 4). In addition to the localized release of VEGF, extracellular regulate bone development or remodelling and vice versa. In vitro study
matrix associated proteins, cysteine-rich angiogenic protein 61/CNN1 demonstrated that conditioned medium of osteocyte cells could stimulate
and connective tissue growth factor/CNN2 [73], together with IL-8 are myogenic differentiation of C2C12 myoblasts. [75] (Fig. 4). Moreover,
elevated after exercise, and these molecules have been proposed to play exercised induced mechanical loading has been shown to induce pro-
important roles in skeletal angiogenesis by activating endothelial cell duction of IGF-1, VEGF, and hepatocyte growth factor in osteocytes cell
proliferation, capillary tube organization, and extracellular matrix line, which may play roles in regulating muscle growth [76,77]. Impor-
remodelling. Finally, the production of ANGPTL4 in exercised muscle tantly, physical training also induces the production of osteocalcin
further enhances the angiogenesis in skeletal muscle, and it also increases (OCN), an osteoblast-derived hormone which was shown to promote
vascular permeability and lipid metabolism muscle. These secretory adaptation to exercise in mice [133]. Finally, it was also found that older
angiogenic factors in all produce an enhanced angiogenic effect in adults with regular exercise expressed an increased activity of mito-
muscle, allowing more blood being supplied to the muscle and more chondrial oxidative enzymes and expression of mitochondrial biogenesis
efficient nutrient delivery to the muscle tissue, an important function in genes such as PGC-1, NRF-1, and TFAM, suggesting that physical training
preventing and delaying the progress of sarcopenia [74] (Fig. 4). is able to enhance and even restore mitochondria function and homeo-
Finally, it is a well-known fact bone and muscle have a very close stasis via direct or indirect stimulation of mitochondria biogenesis
working relationship as such secretory factors from muscles are known to (Fig. 4) [78].

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J.H.-t. Lo et al. Journal of Orthopaedic Translation 23 (2020) 38–52

Figure 4. A schematic illustration of alleviating sarcopenia via exercise. Exercise stimulates muscular contraction which in turn stimulate myocytes to produce
myokines that can enhance muscle innervation, stimulate angiogenesis in muscle, and stimulate satellite cell proliferation and differentiation. Exercise also stimulates
the bones directly via mechanical loading or indirectly via muscular contraction. Stimulation of the bones by exercise activates osteocytes to produce osteokines that
can promote satellite cells proliferation and differentiation, promote muscle growth and induce mitochondria biogenesis. The overall effects of myokines and
osteokines switch the microenvironment towards an anti-inflammatory spectrum that supports angiogenesis, neurogenesis, and myogenesis.

Table 3
Pros and cons of sarcopenia therapeutic strategies.
Current strategies Treatment Pros Cons Reference

Nutritional Protein supplements Improve the muscle mass Not improve the muscle strength and physical performance [109]
supplementation Essential amino acid (EAA) Improve the muscle mass Not improve the muscle strength and physical performance [110]
supplementation in elder women
β-hydroxy β-methylbutyric Not consistent in several studies regarding muscle mass, strength and physical performance. [100],
acid (HMB) [111],[112]
supplementation
Fatty acid supplementation Improved both muscle volume and physical Need further investigation on the dosage and frequency use [89],[113]
performance
Exercise Resistance training Increased muscle mass and strength, skeletal Motivation to exercise in older adults is low [7]
muscle protein synthesis and muscle fibre size Highly dependent on patients' mobility
and improvement in physical performance
Aerobic exercise Increase mitochondrial volume and activity [7]
Medications ACE inhibitors Some evidence for increased exercise capacity Renal function needs monitoring [7]
Myostatin inhibitors Enhance muscle lean mass No conclusive idea on muscular strength and physical [114]
performance improvement.
Testosterone May increase muscle strength and physical Side effect, such as CVDs, fluid retention, gynaecomastia, [115]
performance and decrease fat mass and worsening of sleep apnoea, polycythaemia, and
hospitalization in older adults. acceleration of benign or malignant prostatic disease can be
observed
Growth hormone Increased lean tissue mass and decreased fat Side effects may be induced fluid retention, orthostatic [115,116]
mass hypotension, cancer induction.

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J.H.-t. Lo et al. Journal of Orthopaedic Translation 23 (2020) 38–52

Limitation of physical exercise in sarcopenia treatment and found among differentiated cells in the whole body after develop-
ment. Their main function is to enable healing, growth and replacement
Despite its effectiveness as a sarcopenia therapeutic regime, exercise of cells that are lost everyday [119]. The more well-known examples of
intervention is only available to patients or elderly who are reasonably adult stem cells include mesenchymal stem/stromal cells (MSCs), neural
mobile, in other words, exercise intervention is not expected to benefit stem cells, haematopoietic stem cells, and satellite cells [108,119–121].
bedridden patients despite the fact that these are the patients who As sarcopenia is a muscular degenerative disease in which loss of Pax7
needed such intervention the most (Table 3). Furthermore, as physical satellite cells was known to attribute to sarcopenia progression, it is
abilities vary from patients to patients, it is essential to customize exer- therefore sensible to derive and expand Pax7 satellite cells followed by
cise regime for individual patient to maximize its beneficial effect, transplantation of sufficiently expanded satellite cells into sarcopenic
making physical training for a huge population of patients unrealistic and muscle [121,122]. However, such transplantation strategy did not take
difficult. As such other sarcopenia interventions such as whole-body into account of the proinflammatory environment in aged muscle, which
electricity myostimulation and vibration have been proposed as poten- is detrimental for the transplanted satellite cells. Furthermore, the pop-
tial emerging therapeutic interventions which are able to cater to the ulation of Pax7 satellite cells present in the muscle is too little, making
needs of larger group of patients. However, more trials with larger pa- isolation and expansion in vitro a huge challenge [121,122]. More
tient population will be needed to effectively determine their efficacy. importantly, in the aspect of pharmaceutical manufacturing, the Euro-
pean Medicines Agency have set Good Manufacturing Practice guidelines
New therapeutic approaches – the pros and cons of stem cell transplantation for Advanced Therapy and Medicinal Products, which stated the impor-
and potential alternatives in sarcopenia tance of having proper quality control measures to stability in medicinal
products, in this case Pax7 satellite cells. However, it has been reported
Despite potential novel interventions are being developed in a timely by multiple research groups that satellite cell culture is extremely un-
manner, the number of effective options available against sarcopenia till stable under in vitro culture condition with Pax7 expression and Pax7
date is still restricted solely to exercise as pharmaceutical intervention positive cells dropping with every cell passage [123]. Hence, to effec-
options for sarcopenia is limited and ineffective as it is a multifactorial tively apply satellite cells in sarcopenia treatment, it is paramount to
age-associated condition (Fig. 1) (Table 3). Hence, novel therapeutic resolve the issue on how to effectively derive and expand satellite cells
interventions that are able to concurrently promote mitochondria without losing their pax7 positivity.
biogenesis or restore mitochondrial functions, reduce age-associated
inflammation response in muscle tissue, and promote muscle tissue Mesenchymal stem/stromal cells
regeneration and thereby restoring muscle strength must be developed to
elicit an effective treatment or synergistic effect when used alone or MSCs on the other hand are attractive stem cells to be used in ther-
concurrently with exercise. apeutics development owing to their high abundance and presence in
Regenerative medicine and stem cell therapy are attractive thera- many tissues such as fat, bone marrow, dental pulp, and umbilical cord
peutic intervention strategies for age-associated conditions such as [119,124,125]. Moreover, MSCs are easily expandable in vitro and hence
neurodegenerative diseases and cardiovascular diseases, and so on owing MSCs are used in many clinical trials targeting a huge range of diseases
to their ability to regenerate and repair damaged parts of the body. Stem and conditions from neurodegenerative diseases such as Parkinson's
cells are defined as cells with infinite replication capabilities and the disease and Alzheimer's disease, autoimmune disease such as multiple
ability to differentiate into mature somatic cells such as neurons and sclerosis to injury conditions such as spinal cord injury and stroke
muscle [108]. Therefore, in view of the aetiology of sarcopenia, stem cell [126–130]. Interestingly, many MSC transplantation/therapeutic effects
transplant could be a potential therapeutic strategy. However, that brings were found to be mainly owing to their immune modulating effects that
out numerous therapeutic associated questions such as the type of stem include the production of anti-inflammatory cytokines such as IL-10 and
cells to be use, the safety and efficiency of stem cells, and most impor- IL-13 [126,127,129]. In addition, MSCs have also been reported to
tantly in the pharmaceutical manufacturing process, how are the stem secrete basic fibroblast growth factor, VEGF, monocyte chemotactic
cells defined and what are the quality control in placed to ensure product protein 1 which are also known to have a neuro-supportive effect [131,
consistency and stability? 132]. This creates an anti-inflammatory microenvironment which is
beneficial for endogenous stem cells in the damaged tissue to carry out
Embryonic stem cells and induced pluripotent stem cells essential repair and thereby restoring tissue function. Given the proin-
flammatory microenvironment and innervation condition in aged muscle
Up till now, there are three main types of stem cells, namely em- which attributes to sarcopenia progression, transplantation of MSCs
bryonic stem cells (ESCs), inducedpluripotent stem cells (iPSCs) and might be able to tip the proinflammatory microenvironment in aged
adult stem cells. ESCs and iPSCs are defined as pluripotent stem cells with muscle to an anti-inflammatory microenvironment which is beneficial for
the potential to give rise to tissues from three primary germ layers. the endogenous satellite cells to carry out muscle regeneration while at
However, unlike ESCs which are mainly derived from the inner cell mass the same time stimulating muscular innervation by the peripheral ner-
of the blastocyst, which is a stage of preimplantation embryo that usually vous system. It was also suggested that MSC could mediate mitochondria
occurs 5–6 days after fertilization, iPSCs are man-made pluripotent stem transplantation into aged cells which could have a therapeutic benefit by
cells that are produced by introducing pluripotency genes, such as Sox2, restoring mitochondrial function in both the muscle cells and neuronal
Klf4, Oct3/4 and c-myc, which are collectively known as Yamanaka cells in aged muscle. However, the efficiency and effects of mitochondria
factors, into somatic cells and reprogramming them back to a pluripotent transplant by MSCs remain to be debated. Most importantly, as protocol
state [108,117,118]. However, since the beginning of the use of ESC- for MSCs manufacturing is more established it is easier from the
s/iPSCs in research, not only are many ethical restrictions are being manufacturing point of view to set up in-process quality control param-
formed in place that limit the application of ESCs/iPSCs in therapeutic eters to minimize batch to batch variation in MSCs, potentially making
interventions for human, the safety concern over the formation of tera- them the more suitable candidate for cellular transplantation in
toma by ESCs/iPSCs in transplanted patient is also a major concern that sarcopenia.
limits the medical application of ESCs/iPSCs. Yet, cellular transplantation, such as organ transplantation, involves
the administration of cells which could come from a foreign source, in
Somatic or adult stem cells other words, to allow the transplantation to work, patients might need to
undergo vigorous regime of steroids to improve the survival of cellular
Somatic or adult stem cells on the other hand, are undifferentiated transplant in their body, that can be detrimental to the body. Hence, to

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J.H.-t. Lo et al. Journal of Orthopaedic Translation 23 (2020) 38–52

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