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R E S E A R C H A R T I C L E Open Access
Nicotinamide mononucleotide
supplementation enhances aerobic
capacity in amateur runners: a randomized,
double-blind study
Bagen Liao
1*†
, Yunlong Zhao
2†
, Dan Wang
1,2
, Xiaowen Zhang
3
, Xuanming Hao
4
and Min Hu
1
Abstract
Background: Recent studies in rodents indicate that a combination of exercise training and supplementation with
nicotinamide adenine dinucleotide (NAD
+
) precursors has synergistic effects. However, there are currently no
human clinical trials analyzing this.
Objective: This study investigates the effects of a combination of exercise training and supplementation with
nicotinamide mononucleotide (NMN), the immediate precursor of NAD
+
, on cardiovascular fitness in healthy
amateur runners.
Methods: A six-week randomized, double-blind, placebo-controlled, four-arm clinical trial including 48 young and
middle-aged recreationally trained runners of the Guangzhou Pearl River running team was conducted. The
participants were randomized into four groups: the low dosage group (300 mg/day NMN), the medium dosage
group (600 mg/day NMN), the high dosage group (1200 mg/day NMN), and the control group (placebo). Each
group consisted of ten male participants and two female participants. Each training session was 40–60 min, and the
runners trained 5–6 times each week. Cardiopulmonary exercise testing was performed at baseline and after the
intervention, at 6 weeks, to assess the aerobic capacity of the runners.
Results: Analysis of covariance of the change from baseline over the 6 week treatment showed that the oxygen
uptake (VO
2
), percentages of maximum oxygen uptake (VO
2max)
, power at first ventilatory threshold, and power at
second ventilatory threshold increased to a higher degree in the medium and high dosage groups compared with
the control group. However, there was no difference in VO
2max
,O
2
-pulse, VO
2
related to work rate, and peak power
after the 6 week treatment from baseline in any of these groups.
Conclusion: NMN increases the aerobic capacity of humans during exercise training, and the improvement is likely
the result of enhanced O
2
utilization of the skeletal muscle.
Trial registration number: ChiCTR2000035138.
Keywords: Exercise training, NMN supplementation, Ventilatory threshold, Aerobic capacity
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* Correspondence: bagen2015@163.com
†
Yunlong Zhao is joint first author. Yunglong Zhao and Bagen Liao have
equal contributions.
1
Department of Sports Medicine, Guangzhou Sport University, Guangzhou
510150, China
Full list of author information is available at the end of the article
Liao et al. Journal of the International Society of Sports Nutrition (2021) 18:54
https://doi.org/10.1186/s12970-021-00442-4
Introduction
Nicotinamide adenine dinucleotide (NAD
+
) is pivotal to
physiological processes, not only as the coenzyme of cel-
lular oxidation–reduction reactions but also for the acti-
vation of NAD
+
-consuming enzymes, such as sirtuins,
poly-ADP-ribose polymerases (PARPs), cADP-ribose
synthases, NADase (CD38), and mono-ADP-ribose
transferases (ARTs) [1]. NAD
+
participates in more than
50% of all physiological processes, including mitochon-
drial biogenesis, cardiovascular protection, neuroprotec-
tion, oxidative stress, DNA damage repair, stem cell
rejuvenation, and inflammation [2]. Low NAD
+
levels
are associated with age-associated physical disability and
diseases, such as metabolic syndrome and cardiovascular
disease [1–3]. The NAD
+
salvage pathway, which utilizes
NAD
+
precursors, is the predominant mechanism for
maintaining cellular NAD
+
levels in rodents and humans
[1]. Among a diverse range of NAD
+
precursors, nico-
tinamide riboside (NR) and nicotinamide mononucleo-
tide (NMN), two forms of water-soluble vitamin B
3
, are
the two that have been studied in a surge of NAD
+
pre-
cursor research in recent years due to their safety. Sup-
plementation with NR and supplementation with NMN
have shown a dose-dependent increase in cellular NAD
+
levels in a variety of tissues in rodents and humans [4–
6]. Accordingly, replenishment of depleted NAD
+
pools
by NR (mainly at the dose of 300 or 400 mg/kg/d in
mice or rats) or NMN (mainly at doses of 100–500 mg/
kg/d in mice) alleviates pathologic states in rodent
models of age- or diet-induced decline in physical func-
tion, metabolic dysfunctions, neurodegenerative diseases,
cardiomyopathy, and myocardial and cerebral ischemic
injury [2,6]. In addition, NMN supplementation im-
proves energy expenditure, physical activity, and neur-
onal function in a dose-dependent manner [7,8].
Nevertheless, clinical studies have shown that the effects
of NR (dosages from 500 mg/d to 2000 mg/d; durations
of 1 day to 3 months) on skeletal muscle, cardiovascular
function, and physical function in the elderly and obese
are limited [4]. However, the NAD
+
precursor nicotinic
acid (NA), an effective pharmacological drug with indi-
cations for lowering triacylglycerol levels and dilating
blood vessels [9], significantly improved skeletal muscle
function in healthy individuals [10] and in patients with
adult-onset mitochondrial myopathy [11,12]. NR and
NMN have many similar pharmacological effects, but
they are also different in a number of aspects. For ex-
ample, in contrast to NMN, NR was observed to be
unstable in rodent plasma [13]. Furthermore, NMN
improved cardiac function in patients with Frie-
dreich’s ataxia (FRDA) cardiomyopathy, whereas NR
did not [14].
Regular exercise improves aerobic capacity, cardiovas-
cular health, metabolic health, and physical function [15,
16], but many of such improvements may be NAD
+
/sir-
tuins-related [17,18]. Exercise training increases the ex-
pression of nicotinamide phosphoribosyltransferase
(NAMPT), the rate-limiting enzyme in the NAD
+
sal-
vage pathway, as well as the levels of NAD
+
and activity
of sirtuins [19,20]. Endurance athletes show a high
NAMPT expression in skeletal muscle [21]. One study
that used a mouse model of maternal obesity [22] re-
ported that 18-day NMN injection and 9 weeks of exer-
cise had similar benefits for reversing metabolic
dysfunction and showed that NMN had stronger effects
on hepatic fat metabolism than did exercise. Deletion of
PARP-1 or CD38, or the inhibitor of CD38 or PARP-1,
improves mitochondrial function and endurance per-
formance in mice [23–25]. Furthermore, overexpression
of muscle NAMPT in combination with exercise in
wild-type mice augmented exercise endurance, max-
imum oxygen uptake (VO
2
max), and mitochondrial re-
spiratory capacity compared with exercise training alone
[23,26]. NR (400 mg/kg/d) and NMN (500 mg/kg/d)
with exercise training increased endurance performance
in healthy young [27] and elderly [17] mice. Neverthe-
less, a decrease in endurance performance from NR
(300 mg/kg/d) in combination with swimming training
was shown in young rats [28]. At present, the effect of
the combination of exercise and NMN supplementation
on cardiovascular fitness in healthy humans has not
been reported. Cardiopulmonary exercise test (CPET) is
the gold-standard method for assessing aerobic fitness.
In this study, we conducted a six-week randomized,
double-blind, four-arm, placebo-controlled clinical trial
to investigate the effect of different doses of NMN sup-
plementation on cardiovascular fitness.
Methods
Subjects
This study was performed at the Key Laboratory of Exer-
cise and Health Promotion of Guangzhou Sport Univer-
sity and was approved by the ethics committee of
Guangzhou Sport University (ethics approval number
2020 LCLL-003). Forty-eight healthy recreationally
trained runners (40 males and 8 females, aged 27–50
years, with regular exercise years of 1–5 years) from the
Guangzhou Pearl River running team were recruited for
the study. All participants were healthy and nonsmokers
who did not drink caffeine or alcoholic drinks and had
no prior use of medication or supplemental nutrients.
Furthermore, all participants gave written informed con-
sent to be included in the study before the initiation of
the study.
Study design
The study was a double-blind, randomized controlled
trial, and it is registered in the Chinese Clinical Trial
Liao et al. Journal of the International Society of Sports Nutrition (2021) 18:54 Page 2 of 9
Registry (ChiCTR2000035138 at http://www.chictr.org.
cn/). Participants were randomly assigned to one of four
groups (each group included ten male participants and
two female participants). Randomization was stratified
for gender. Allocation to nutritional supplementation
with NMN (treatment groups) or placebo (control
group) was concealed to the participants, support staff,
and investigators, except for the quality specialists, dur-
ing the course of the study.
Supplementation
All of the participants were instructed to not change their
habitual diet and daily living routines, and to refrain from
caffeine during the study. The oral supplementation of
powder (with or without NMN) lasted for 6 weeks. The
lower dosage group received one bag with 150 mg NMN
powder twice daily (Bid), the medium dosage group re-
ceived one bag with 300 mg NMN powder Bid, the high
dosage group received one bag with 600 mg NMN powder
Bid, and the control group received one bag with match-
ing placebo powder containing no NMN Bid. The placebo
powder was composed of cranberry powder and malto-
dextrin, and all bags with different NMN were identical in
weight, size, shape, and color. All the materials, including
the placebo powder, were provided by GeneHarbor (Hong
Kong) Biotechnologies Ltd. Participants were asked to
take their supplement (one bag at breakfast and one at
lunch or in the afternoon) before training. To record the
consumption count, any remaining bags were returned to
the study supervisor to ensure compliance to the supple-
mentation protocol every weekend and at the end of the
study.
Training
All participants actively trained during the study period
by adhering to an exercise program. The exercise pro-
gram consisted of 6 weeks of aerobic exercise (running
and cycling), with a single exercise session lasting 40–60
min. The exercise program called for 5–6 of these ses-
sions per week. Furthermore, all participants were re-
quired to run 3–4 times per week and ride the bicycle
twice per week. The exercise intensity was monitored by
heart rate (HR) measurements based on the results of
the CPET at baseline. The target HR ranges of exercise
corresponded to 80–100% VO
2
(80–90% VO
2
for cyc-
ling, 90–100% VO
2
for running) at first ventilatory
threshold (VT
1
) during the first 2 weeks, 90–110% VO
2
(90–100% VO
2
for cycling, 100–110% VO
2
for running)
at VT
1
during the middle 2 weeks, and 90–120% VO
2
(90–110% VO
2
for cycling, 100–120% VO
2
for running)
at VT
1
in the last 2 weeks. The training sessions were
conducted in the afternoon or in the early evening on
working days and in the morning on weekends. The tar-
get HR range was monitored by sports watch (Garmin
Forerunner 245) during exercise and study personnel su-
pervised the training program throughout the study.
Measurement of results
All participants were evaluated by CPET at baseline and
at the end of the six-week experimental intervention
period. On testing day, participants came to the labora-
tory, which had a room temperature set between 20 °C
and 25 °C. Testing began at least 2.5 h after a normal
meal, and participants could not have caffeine or alcohol
for at least 12 h before the measurements.
Anthropometric data
Height and body mass were assessed by a height-weight
meter. Body composition (body fat %) and free-fat mass
(FFM) were assessed by bioelectrical impedance analysis
(Seca mBCA-115, Germany). Body mass index (BMI)
was calculated as weight(kg)/Height(m)
2
.
Cardiopulmonary endurance performance
Cardiopulmonary endurance performance was evaluated
by CPET. The main measuring parameters include car-
diovascular parameters (VO
2
,O
2
-pulse, VO
2
-related to
work rate), ventilatory parameter (V
E
), metabolic param-
eters (respiratory exchange ratio, VT
1
, and VT
2
) and ex-
ercise capacity parameters (workload and power). For
the determination of above parameters, the participants
were required to complete an incremental ramp exercise
test until exhaustion was reached, as indicated on a
cycloergometer (Ergoline ErgoSelect 200, Germany). For
males, the starting workload was 50–100 W, and there
was a continuous increase of 20–30 W per minute. For
females, the starting workload was 50–75 W, and there
was a continuous increase of 15–25 W per minute. The
test was terminated when any three of the five following
criteria were met: volitional fatigue, as indicated by an
inability to maintain a set rate after verbal encourage-
ment was given; HR failing to increase with the increas-
ing workload; an increase in VO
2
< 150 mL/min despite
the workload increasing; a respiratory exchange ratio
(RER) ≥1.10; a Borg rating of perceived exertion > 17.
The gas analyzer system was calibrated according to the
manufacturer’s recommendations before each test. In
this test, a cardiorespiratory function test system (COR-
TEX MetaLyzer®3B, Germany) recorded the HR, heart
rate reserve (HRR), RER, workload, power, oxygen con-
sumption (VO
2
), carbon dioxide production (VCO
2
), ex-
pired minute volume (V
E
), partial pressure of end-tidal
O
2
(PETO
2
), and partial pressure of end-tidal CO
2
(PETCO
2
). A 12-lead electrocardiogram (ECG, Cardio
300 UBE00880, Germany) was continuously recording
during the test. Blood pressure, including systolic blood
pressure and diastolic blood pressure, was measured
every 3 min during the cycling.
Liao et al. Journal of the International Society of Sports Nutrition (2021) 18:54 Page 3 of 9
Data collection and reduction
Measurements of the parameters [VO
2max
,V
Emax
,
HR
max
, HRR, peak workload, and peak power (metabolic
equivalents, Mets)] were recorded according to the Cli-
nician’s Guide to Cardiopulmonary Exercise Testing
statement [29]. O
2
-pulse, VO
2
as a percentage of
VO
2max
, and VO
2
related to work rate (ΔVO
2
/ΔWR)
were calculated (from beginning to VT
1
).
The VT
1
is the first disproportionate increase in the
rate of VCO
2
compared with VO
2
; a significant increase
in the V
E
/VO
2
without a concomitant increase in V
E
/
VCO
2
; or an increase in the PETO
2
with no simultan-
eous decrease in the PETCO
2
[30]. The VT
2
, also called
the respiratory compensation point, is the first dispro-
portionate increase in V
E
compared with VCO
2
, the be-
ginning increase in V
E
/VCO
2
, or the beginning decrease
in the PETCO
2
[30].
Statistical analysis
The statistical analyses were carried out using SPSS
22.0. Baseline data are expressed as the mean and
standard deviation. The differences between baseline
data and post-intervention data are expressed as the
mean and 95% confidence interval (CI). Comparisons
of the baseline data and post-intervention changes
among the four groups were performed using one-
way analysis of variance (ANOVA) followed by
Tukey’s post hoc test to identify significantly different
means. ANOVA for repeated measurements of time
course (pre- and post-intervention) and with or with-
out NMN supplementation was also performed to de-
feat intergroup differences. In cases of a difference,
the baseline measurement was used as the covariate
in each covariance analysis. Cohen’sdwas used to
calculate effect sizes. An effect size of ≤0.2 was con-
sidered as indicating a small clinical effect, 0.5 as in-
dicating a moderate clinical effect, and > 0.8 as
indicating a large clinical effect [31]. Statistical signifi-
cance was indicated by p<0.05.
Results
The combination of exercise and NMN does not change
body mass or alter body composition
All participants completed the required intervention.
The baseline characteristics are shown in Table 1and
Supplementary Table S1. There were no significant dif-
ferences among the four groups. Following the 6 weeks
NMN supplementation in amateur runners, differences
in body mass, BMI, or body fat% were found between
the treatment groups and control group (Table 2).
The combination of NMN and exercise increases VT but
not VO
2max
or O
2−
pulse
No significant changes in HR
max
, RER
max
, HRR, O
2
-
pulse, peak power, peak workload, ΔO
2
/ΔWR, or
VO
2max
were shown between the control and any of the
NMN treatment groups. However, the VO
2
@VT
1
,
%VO
2max
@VT
1
, HR@ VT
1
, power@VT
1
, and
power@VT
2
(Tables S1and S2; Table 3) were increased
significantly from the NMN supplementation compared
with baseline, and the positive effect was in a dose-
dependent manner (Table 4).
Adverse events
During the intervention period, all participants had
taken the NMN or placebo according to the require-
ments, and none of the participants reported an adverse
event. No obvious abnormalities were shown on the
ECG during exercise in the CPET.
Discussion
In rodents, NMN is able to increase cellular NAD
+
con-
tent in dosage ranges from 31.25 mg/kg/d to 500 mg/kg/
d, and it is shown to be safe [2,6,22]. In humans, only
one study of this has been reported, which used a single
dose of 500 mg NMN. In this study, the NMN increased
circulatory NAD
+
and was shown to be safe [32]. Here,
we administrated three dosages (300, 600, and 1200 mg/
d) of NMN supplementation to healthy amateur runners
during a 6-week exercise training program. The main
Table 1 Participant baseline characteristics, including age, exercise years, anthropometric data, and VO
2max
total control Group Lower Dosage Medium Dosage High Dosage P value
Age (years) 35.6 (6.1) 36.1 (6.0) 37.0 (5.7) 35.5 (6.1) 33.5 (6.6) 0.54
Exercise years (years) 2.8 (1.4) 2.7 (1.5) 2.6 (1.4) 2.9 (1.4) 2.8 (1.3) 0.94
Height (cm) 168.4 (6.1) 171.7 (6.3) 166.9 (5.1) 169.0 (6.2) 166.3 (6.3) 0.14
Body mass (kg) 62.5 (8.6) 64.9 (8.1) 62.0 (8.7) 62.5 (11.3) 60.7 (6.1) 0.69
BMI (kg/m2) 22.0 (2.6) 22.0 (2.6) 22.3 (3.2) 21.8 (2.9) 21.9 (1.6) 0.17
FFM (kg) 52.0 (7.5) 53.4 (7.2) 52.2 (7.1) 52.5 (8.4) 50.0 (7.5) 0.16
Body fat % 16.7 (6.7) 17.8 (5.7) 15.5 (6.4) 15.7 (6.6) 17.8 (8.4) 0.97
VO
2max
((L/min) 2.48 (0.49) 2.64 (0.46) 2.54 (0.52) 2.43 (0.45) 2.34 (0.52) 0.56
Note: Data in brackets represent means SD
Liao et al. Journal of the International Society of Sports Nutrition (2021) 18:54 Page 4 of 9
finding of this study is that NMN supplementation dur-
ing exercise improved first ventilatory threshold (VT
1
)
and power@VT
2
without changing the VO
2max
and that
this improvement was dose-dependent.
Exercise combined with NMN did not change body
composition
Our observations indicate that six-week aerobic exercise
with low- to high-dose NMN supplementation did not
alter body mass, FFM, BMI, or body fat%. Both NR [33]
and NMN [7,22] inhibited high-fat diet or age-induced
weight gain and increased energy consumption in mice.
A human study [34] of NR on body composition in
healthy obese middle and older people showed that body
fat % improved, whereas body weight remained un-
changed, and the improvement appeared to be a gender-
dependent. Exercise combined with NR showed no add-
itional improvement in body weight reduction and fat
deposits in young mice compared to exercise only [27].
Considering the good standing of BMI and body fat % of
the participants in this study, no further changes in BMI
and body fat % were expected.
Exercise combined with NMN increases VT but not VO
2max
A recent study on rodents demonstrated that exercise
combined with NMN led to a further increase in run-
ning endurance in healthy young mice [17]. Our results
specifically reveal that 6 weeks of endurance exercise
combined with NMN supplementation in amateur run-
ners enhanced VT
1,
VO
2
, and VO
2max%
but not VO
2max
,
V
Emax
,O
2
-pulse, ΔO
2
/ΔWR, RER, or peak power. In
addition, a large dose of NMN also improved the
power@VT
2.
These results indicate that NMN supple-
mentation was able to further increase the ventilatory
threshold compared to exercise alone. The improvement
may be attributed to an improved ability of O
2
utilization by skeletal muscle, as no changes in VO
2max
and O
2−
pulse and ΔO
2
/ΔWR were observed instead of
improvement of cardiac function. Our data suggest that
skeletal muscle is one of the most sensitive tissues to
NMN in humans.
Table 2 Changes in body composition of the participants after the 6-week intervention
Control Group Lower Dosage Medium Dosage High Dosage Time P value T × D P value
Δbody mass (kg) 0.15 (−0.42, 0.72) 0.07 (−0.44, 0.57) −0.05 (−0.78, 0.68) 0.63 (0.21, 1.04) 0.13 0.27
ΔBMI (kg/m2) 0.05 (−0.14, 0.25) 0.03 (−0.15, 0.21) −0.02 (−0.28, 0.24) 0.23 (0.08, 0.39) 0.11 0.24
ΔFFM (kg) 0.76 (0.17, 1.35) −0.24 (−0.95, 0.46) −0.02 (−0.72, 0.69) 0.31 (−0.23, 0.85) 0.13 0.09
Δbody fat (%) −0.94 (−2.11, 0.24) 0.47 (−0.38, 1.31) 0.03 (−1.04, 1.08) 0.16 (−0.65, 0.96) 0.74 0.16
Note: Δ,The difference between pre and post intervention in mean (95% CI). ANOVA for repeated measurement for interaction of time (T) and dose (D)
Table 3 Changes in cardiopulmonary function of the participants after the 6-week intervention from baseline
control Group Lower Dosage Medium Dosage High Dosage Time Pvalue T × D P value
ΔO2-pulse max (L/min/bpm) 0.73 (−0.23, 1.68) 1.25 (0.23,2.27) 0.82 (0.07, 1.70) 1.17 (0.32, 2.02) < 0.01 0.56
ΔRER max 0.09 (0.00, 0.18) −0.02 (−0.07, 0.07) 0.05 (−0.16, 0.11) 0.03 (−0.08, 0.14) 0.04 0.36
Δ(L/min) 0.18 (0.02, 0.36) 0.23 (0.09,0.37) 0.26 (1.74, 0.35) 0.32 (0.20, 0.43) < 0.01 0.48
ΔPeak power (Mets) 0.72 (−0.04, 1.49) 1.05 (0.45,1.65) 1.18 (0.78, 1.58) 1.45 (0.86, 2.06) < 0.01 0.31
ΔPeak workload (W) 10.9 (−2.47, 24.24) 11.25 (−0.43, 22.93) 13.58 (5.44, 21.7) 13.93 (8.92, 18.95) < 0.01 0.58
ΔHR@VT1 (bpm) 5.8& (0.3, , 11.4) 5.2& (1.1, 9.2) 12.8 (7.8, 17.8) 16.0 (10.4, 21.5) < 0.01 < 0.01
ΔO2-pulse @VT1 (L/min/bpm) 0.55 (−0.37, 1.46) 1.17 (0.71,1.62) 0.92 (0.17, 2.20) 2.00 (1.23, 2.77) < 0.01 0.10
Δ@VT1 (L/min) 0.17#& (0.09, 0.24) 0.24& (0.18,0.30) 0.33 (0.25, 0.41) 0.47 (0.34, 0.60) < 0.01 < 0.01
ΔPower @AVT1 (Mets) 0.69#& (0.35, 1.03) 1.06& (0.80,1.31) 1.41& (1.02, 1.79) 2.13 (1.56, 2.69) < 0.01 < 0.01
Δ%@VT1 (%) 2.1& (−0.85, 1.49) 3.5& (0.05,7.00) 6.5 (3.62, 9.43) 10.3 (7.61,13.05) < 0.01 < 0.01
ΔHR@VT2 (bpm) 5.6 (1.9, 9.4) 6.7 (3.2, 10.2) 10.8 (4.5, 17.2) 12.4 (4.4, 20.5) < 0.01 0.23
ΔO2-pulse @VT2 (L/min/bpm) 0.55 (−0.37, 1.47) 1.58 (0.95,2.22) 0.50 (0.04, 1.91) 1.67 (0.72, 2.62) < 0.01 0.16
Δ@VT2 (L/min) 0.20 (0.03, 1.49) 0.39 (0.26,0.52) 0.33 (0.22, 0.44) 0.44 (0.29, 0.58) < 0.01 0.06
ΔPower @VT2 (Mets) 0.78 (0.07, 1.49) 1.78 (1.20,2.35) 1.56 (1.00, 2.11) 2.04 (1.34, 2.73) < 0.01 0.03
Δ%@VT2 (%) 1.55 (−1.75, 4.84) 6.67 (3.20,10.10) 4.25 (1.28, 7.22) 6.58 (3.57, 9.59) < 0.01 0.06
ΔO2/ΔWR slope (ml/min/w) 0.11 (−0.58, 0.79) 0.44 (−0.16,1.04) 0.58 (0.01, 1.16) 0.69 (0.06, 1.45) < 0.01 0.56
Note: The difference of parameter between pre and post intervention among four groups were performed using one-way ANOVA. #VS medium dosage, P< 0.05,
&VS large dosage, P< 0.05
ANOVA for repeated measurement for interaction of time (T) and dose (D). bpm, beat per minute
Liao et al. Journal of the International Society of Sports Nutrition (2021) 18:54 Page 5 of 9
It is well-known that endurance exercise increases aer-
obic capacity through improving mitochondrial function,
vascular endothelium function, and capillary density of
muscle, independent of age [35]. NMN administration
had also been reported to improve mitochondrial func-
tion in various metabolic organs, including skeletal
muscle [36,37], to improve vascular endothelium func-
tion [17,38], to promote neoangiogenesis and increase
capillary density, blood flow, and soluble oxygen levels,
and to switch skeletal muscle fibers to the more oxida-
tive type in elderly or aged mice [17,18]. These
exercise-induced adaptive changes undoubtedly contrib-
ute by increasing the anaerobic threshold [39]. Exercise
combined with NMN administration further increased
exercise endurance and rebuilt the skeletal muscle capil-
lary number and density to youthful levels in elderly
mice, and it significantly increased the capillary/myofiber
ratio in the quadriceps compared to NMN alone or ex-
ercise alone in young mice [17].
Although NMN supplementation improved endothelium
function and reduced vessel wall stiffness in aged rodents
[38] and restored cardiac function in cardiac pathologies,
such as cardiomyopathy and ischemia/reperfusion (I/R)
cardiac injury [40,41], research shows that NMN supple-
mentation does not affect cardiac function or cardiac capil-
lary density in elderly mice [17]. Our results also indicate
that exercise with NMN supplementation had no added ef-
fect on cardiac function in amateur runners.
Dose-dependent relationship
It was reported in mice that lower dosages of NMN (100
mg/kg/d) were better compared with larger doses (300
mg/kg/d) for body weight, body composition, insulin sen-
sitivity, bone mineral density, and physical activity [7], and
treatment with 62.5 mg/kg NMN was better than that
with 125–500 mg/kg NMN for ischemia-induced brain
damage [8]. Furthermore, a lower dose of NMN led to an
improvement in female infertility with enhanced oocyte
quality [42]. According to an equivalent surface area dose
(mg/kg body weight) conversion, a human dose is ap-
proximately one-tenth of that for a mouse [7]. Therefore,
50, 100, and 200mg/kg/d of NMN for mice is approxi-
mately 300, 600, 1200 mg/d for humans of 60 kg body
weight. In contrast, our human study showed that exercise
combining with NMN supplementation increases VT in a
dose-dependent and the large dose of NMN had better ef-
fect. Of note, we also measured physical function and the
results show that exercise combined with NMN supple-
mentation had no effect on grip strength, push-up, or sit-
and-reach compared with exercise only, but 600 mg/d
NMN, not 1200 mg/d NMN, significantly improved single
leg stance test results (Supplementary Tables S3–S5). In
one study, it was reported that there was an overdose
NAD
+
precursor reduced skeletal muscle NAMPT con-
tent through negative feedback [43]. All of these data sug-
gest that for NMN, there may not exist as one-size-fits-all.
Side effects
Pharmacological dose of NA and nicotinamide (NAM)
may result in painful flushing, liver damage and NAM
exhibit sirtuin-inhibiting effects [44,45], whereas NMN
and NR exhibit better pharmacokinetic and pharmaco-
logical properties [17,46–48]. In rodent, long-term
NMN administration from 100 to 300 mg/kg/d did not
result in any obvious side effects [7]. In human, single
oral dose ranging from 100 to 500 mg NMN was safe
and had no significant deleterious effects in healthy indi-
vidual [32]. In this study, 300–1200 mg, a day, 6 week
did not have any obvious adverse symptoms and abnor-
mal ECG.
Table 4 Analysis of the effect sizes (Cohen’s d), expressed as the mean (95% CI) and p value, for differences in adjusted means
between the groups after the intervention
Lower VS control Medium VS control High VS control Medium VS Lower High VS Lower High VS Medium
ES
(95%CI)
P
value
ES
(95%CI)
P
value
ES
(95%CI)
P
value
ES
(95%CI)
P
value
ES
(95%CI)
P
value
ES
(95%CI)
P
value
VO2@VT1 0.61 0.16 1.45 <0.01 2.62 <0.01 0.83 0.05 2.03 <0.01 1.20 0.01
(L/min) -0.25,1.42 0.48,2.30 1.43,3.62 -0.03,1.63 0.99,2.93 0.30,2.03
%VO2max@VT1 0.34 0.42 0.89 0.04 1.56 0.01 0.55 0.19 1.22 0.01 0.69 0.10
(%) -0.50,1.15 0.00,1.71 0.58,2.45 -0.28,1.34 0.31,2.04 -0.16,1.49
HR@VT1 0.1 0.81 0.86 0.05 1.19 0.01 0.72 0.09 1.06 0.02 0.36 0.38
(bpm) -0.72,0.92 -0.02,1.68 0.26,2.03 -0.13,1.52 0.17,1.87 -0.46,1.15
Power @VT1 0.56 0.18 1.15 0.01 2.30 <0.01 0.58 0.16 1.74 <0.01 1.17 0.01
(Mets) -0.29,1.38 0.23,1.99 1.18,3.25 -0.25,1.38 0.75,2.61 0.27,1.99
Power @VT2 0.99 0.02 0.77 0.07 1.25 0.01 0.22 0.59 0.26 0.52 0.48 0.24
(Mets) 0.09,1.82 -0.10,1.59 0.32,2.09 -0.59,1.01 -0.55,1.05 -0.35,1.27
bpm beat per minute
Liao et al. Journal of the International Society of Sports Nutrition (2021) 18:54 Page 6 of 9
Limitations
In this study, one limitation was conducted the CPET
on a cycloergometer instead of a treadmill. Taking into
account the modality including cycling and the advan-
tages of a cycloergometer recording the ECG, we had
chosen a cycloergometer. However, the running was the
main form of modality, CPET on a treadmill ergometer
would be a better way to assess aerobic fitness. In
addition, it was reported that values of VO
2max
and the
VT in active runners or amateur triathletes were ~ 10%
higher on treadmill than cycle ergometry [49], thus we
prescribed targed HR during running training corre-
sponding to 100–120% VO
2
at VT
1
measured in cycle
ergometer. Nevertheless, the intensity prescription for
running training in the context of our study subjects did
not rule out bias because of individual differences of
interchangeability between tests.
The second limitation was that the changes of blood
lactate (especially blood lactate at the peakpower) was
not simultaneously measured during CPET. NMN sup-
plementation had been reported to reduce post-exercise
blood lactate with improvement in endurance in mice
[17]. Another research study showed that three-week
swimming training combined NR administration (300
mg/kg/d) reduced glucose concentration and maximal
blood lactate accumulation in rats with a decrease in ex-
ercise endurance [27]. The measurement of blood lactate
could provide another insight into the metabolic adapta-
tions underlying the VT-improving effect.
Another limitation of the current investigation was
separate female from male due to a limited number of
female participants. Additional studies are needed to de-
termine if there exist gender difference and improve-
ment in vascular endothelium function, and whether the
combination of NMN supplementation and exercise
leads to increases in capillary density, blood flow, and
mitochondrial function.
Conclusion
The results of this study reveal that exercise training
combining with the supplementation of NMN further
lift ventilatory threshold in amateur runners, the benefit
is dose-dependent and muscle-related.
What are the new findings
▸The combination of NMN supplementation and
exercise further improves ventilatory threshold even
among healthy young and middle-aged people.
▸The improvement of aerobic capacity is in a dosage-
dependent, large dosage of NMN with exercise has
better effects.
▸The improvement is muscle, not cardiac, related.
How might impact on clinical practice in the near future
▸NMN as adjunct treatment may help to improve
performance during exercise training.
▸Exercise training combining with NMN
supplementation may be a novel and practical strategy
to increase endurance performance of athletes.
Supplementary Information
The online version contains supplementary material available at https://doi.
org/10.1186/s12970-021-00442-4.
Additional file 1: Table S1. Baseline cardiopulmonary function
parameters of the participants. Table S2. Changes in cardiopulmonary
function after 6-week intervention from baseline. Table S3. Baseline re-
sults of the physical function test. Table S4. The change in the physical
function test results at 6-week intervention from baseline. Table S5. Ana-
lysis of the effect sizes (Cohen’s d), expressed as the mean (95% CI) and p
value, for differences in adjusted means between the groups after the
intervention.
Acknowledgements
We gratefully acknowledge the contribution of professor Jun Wang
(GeneHarbor (Hong Kong) Biotechnologies Ltd ) to the research.
Availability of supporting data
The data sets used and/or analyzed during the current study are available
from the corresponding author on reasonable request.
Authors’contributions
The quality control, Min Hu; Experimental design, Bagen Liao, Yunlong Zhao;
The measurement of cardiovascular fitness performance and physical
function, Yunlong Zhao and Dan Wang; Training supervision, Xuanming Hao,
Yunlong Zhao; Supplementation supervision, Dan Wang; Data collections:
Xiaowen Zhang; Manuscript, Revisions, Bagen Liao, Yunlong Zhao; Funding,
Min Hu, Bagen Liao. All authors read and approved the final manuscript.
Authors’information
Bagen Liao, professor in sports medicine, head of the Department of Sports
Medicine at Guangzhou Sport University.
Min Hu, professor in sports physiology, vice principal of Guangzhou Sport
University.
Xuanming Hao,professor in sports physiology at the College of Physical
Education, South China Normal University.
Xiaowen Zhang, researcher in sports training at Guangzhou Institute of
Sports Science.
Yunlong Zhao, Phd student.
Dan Wang, graduate student.
Funding
This research was supported by Grant 2020YFC2002900 from The National
Key Research and Development Program of China.
Declarations
Ethics approval and consent to participate
The study was approved by the ethical committee of Guangzhou Sport
University (ethics approval number 2020 LCLL-003).
Consent for publication
Written informed consent for publication consent of their clinical details
(included in the informed consent form) was obtained from the subjects.
Competing interests
None of the authors had a conflict of interest.
Liao et al. Journal of the International Society of Sports Nutrition (2021) 18:54 Page 7 of 9
Author details
1
Department of Sports Medicine, Guangzhou Sport University, Guangzhou
510150, China.
2
Guangdong Physical Fitness and Health Management
Association, Guangzhou 510310, China.
3
Guangzhou Institute of Sports
Science, Guangzhou 510620, China.
4
South China Normal University,
Guangzhou 510631, China.
Received: 22 December 2020 Accepted: 18 May 2021
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