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44.guadalupegrau METS 2017
44.guadalupegrau METS 2017
DOI: 10.1111/sms.12881
ORIGINAL ARTICLE
1
Xlab, Department of Biomedical
Sciences, Faculty of Health
Aerobic interval training (AIT) improves the health of metabolic syndrome patients
Sciences, Center for Healthy (MetS) more than moderate intensity continuous training. However, AIT has not been
Aging, University of Copenhagen, shown to reverse all metabolic syndrome risk factors, possibly due to the limited dura-
Copenhagen, Denmark
2
tion of the training programs. Thus, we assessed the effects of 6 months of AIT on
ImFINE Research Group, Department of
Health and Human Performance, Technical cardio-metabolic health and muscle metabolism in middle-aged MetS. Eleven MetS
University of Madrid, Madrid, Spain (54.5±0.7 years old) underwent 6 months of 3 days a week supervised AIT program
3
Exercise Physiology Laboratory at on a cycle ergometer. Cardio-metabolic health was assessed, and muscle biopsies
Toledo, University of Castilla-La Mancha,
were collected from the vastus lateralis prior and at the end of the program. Body fat
Toledo, Spain
4
Department of Sport Science, European
mass (−3.8%), waist circumference (−1.8%), systolic (−10.1%), and diastolic (−9.3%)
University of Madrid, Madrid, Spain blood pressure were reduced, whereas maximal fat oxidation rate and VO2peak were
significantly increased (38.9% and 8.0%, respectively; all P<.05). The remaining
Correspondence
Ricardo Mora-Rodríguez, Exercise components of cardio-metabolic health measured (body weight, blood cholesterol,
Physiology Laboratory at Toledo, triglycerides, and glucose) were not changed after the intervention, and likewise, insu-
University of Castilla-La Mancha, Toledo,
lin sensitivity (CSi) remained unchanged. Total AMPK (23.4%), GLUT4 (20.5%),
Spain.
Email: [email protected] endothelial lipase (33.3%) protein expression, and citrate synthase activity (26.0%)
Funding information
increased with training (P<.05). Six months of AIT in MetS raises capacity for fat oxi-
Spanish Ministry of Economy and dation during exercise and increases VO2peak in combination with skeletal muscle im-
Competiveness, Grant/Award Number: provements in mitochondrial enzyme activity. Muscle proteins involved in glucose,
DEP2014-52930-R
fat metabolism, and energy cell balance improved, although this was not reflected by
parallel improvements in insulin sensitivity or blood lipid profile.
KEYWORDS
aerobic interval training, metabolic syndrome, muscle metabolism
Scand J Med Sci Sports. 2018;28:585–595. wileyonlinelibrary.com/journal/sms © 2017 John Wiley & Sons A/S. 585 |
Published by John Wiley & Sons Ltd
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586 GUADALUPE-GRAU et al.
acid (FA) uptake, mitochondrial FA oxidation,7 basal met- phosphorylation, glycogen content, hexokinase II (HKII), EL,
abolic rate and is the primary tissue responsible for whole- LPL, and HSL). We also aimed to test whether the intervention
body glucose disposal.8 Studies performed by us and others is effective to induce mitochondrial biogenesis (citrate synthase
suggest that skeletal muscle energy metabolism may be dys- activity, CS), and to increase the ability to oxidize fat at the
regulated in metabolic disease patients due to decreased whole-body level (maximal fat oxidation capacity, MFO) and
mitochondrial function and/or density,9,10 or impaired FA the mitochondrial level (β-hydroxyacyl-CoA-dehydrogenase
oxidation that results in the accumulation of intramuscular activity, HAD) in a group of middle-aged MetS with a previ-
lipids.11,12 Interestingly, 4 months of aerobic interval training ous experience in AIT (4 months). Ultimately, results of this
(AIT), that combines periods of light to moderate intensity study may help to design training based lifestyle intervention
(~70% HRmax) with sets of vigorous intensity (~90% HRmax), programs aimed at improving health among MetS patients.
is a time efficient way to increase aerobic capacity, reverse
risk factors, and induce mitochondrial biogenesis in middle-
aged MetS individuals.9,13 Other AIT studies report mixed
2 | M ATERIAL AND M ETHOD S
results regarding muscle insulin sensitivity, reflected by dif-
2.1 | Participants and study design
ferent effects on the total protein levels of the glucose trans-
porter GLUT4, glycogen, hexokinase II (HKII), and insulin Eleven metabolic syndrome patients (eight men and three
receptor mediated signaling.14-16 However, the main skeletal post-
menopausal women) with a previous experience in
muscle signaling cascades activated by exercise have not AIT9 volunteered to participate in the study. This study was
been sufficiently investigated in response to aerobic interval conducted between December 2012 and June 2013, with a
training in MetS patients. During muscle contraction, the rate minimum detraining period of 2 months from the previous
of ATP turnover increases and AMPKα phosphorylation on AIT program. Their mean±SD age, height, body weight,
its threonine residue 172 (pThr172-AMPKα) can be elicited BMI, body fat mass, and VO2peak were 54.5±8.7 years old,
by both moderate17 and high-intensity exercise.18-20 When 1.65±0.18 m, 90.1±14.5 kg, 32.8±1.9 kg·m−2, 31.8±3.4 kg,
the AMPK signaling cascade is activated, a higher peroxi- and 25.6±7.2 mL·kg−1·min−1. Written consent was given by
some proliferator-activated receptor gamma coactivator 1-α the participants after they were fully informed about the ex-
(PGC-1α) mRNA expression is induced leading to a stimula- ercise program and the experimental procedures, and the pos-
tion of mitochondrial biogenesis and fiber type switching to- sible benefits and risks associated with the experiment. All
ward type I fibers.21,22 Another well-characterized upstream the participants reported no cardiovascular or renal disease,
modulator of PGC-1α is the calcium/calmodulin-dependent peripheral vascular disease, and any disease associated with
protein kinase II (CaMKII) signaling pathway, which is ac- exercise intolerance. The study was approved by the local
tivated by the increased intracellular calcium flux with ex- Hospital’s Ethics Committee.
ercise.20,23 This signaling cascade is also thought to mediate Owing to the special characteristics of our participants
the expression of genes controlling FA oxidation, oxidative (middle-aged MetS willing to have a muscle biopsy taken),
enzymes, and GLUT4 among others.20 it was not possible to gather a sufficient number of patients
On the other hand, muscle lipases hydrolyze blood tri- to conduct a randomized controlled trial. In consequence, a
glycerides, triglyceride-rich lipoproteins, and chylomicrons quasi-experimental reversal design was used, in which each
supplying the myocyte with fatty acids to oxidize or store. subject acted as their own control.27
Upon production by the underlying parenchymal cells, lipo-
protein lipase (LPL) is transported and attached to the capil-
2.2 | Preliminary testing
lary endothelium by the protein GPIHBP1 forming endothelial
lipase (EL). Overexpression of EL decreases high- density All volunteers underwent medical screening to exclude indi-
lipoprotein (HDL) cholesterol levels, whereas blocking its viduals with symptoms or signs of cardiorespiratory disease.
action increases concentrations of HDL cholesterol.24 EL Prior to the start of the experiment, participants underwent
has been shown to be higher in skeletal muscle of endurance- a cycling graded exercise test until volitional exhaustion
trained middle-aged men compared to age-matched sedentary in an electrically braked cycle ergometer (Ergoselect 200;
men.25,26 However, the potential effects of long-term exercise Ergoline, Bitz, Germany). Integrated standard 12-lead ECG
training on LPL, EL, and other lipases important for intramus- (Quark T12, Cosmed, Rome, Italy) and blood pressure were
cular lipid droplets mobilization like the hormone-sensitive monitored in every stage to ensure that all subjects had a nor-
lipase (HSL) are not fully elucidated in MetS patients. mal cardiovascular response to exercise. During the maximal
In this study, we tested if 6 months of AIT improves test, O2 consumption was measured by indirect calorim-
metabolic risk factors, insulin sensitivity and upregulates etry (Quark B2; Cosmed), and peak oxygen consumption
key proteins in skeletal muscle energy metabolism (Thr172- (VO2peak) and peak heart rate (HRpeak) were assessed as ex-
AMPK/Ser221- ACCβ phosphorylation, Thr286-CaMKII plained elsewhere.9
GUADALUPE-GRAU et al.
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587
enzymatic β-hydroxy-acyl-CoA-dehydrogenase activity was significant when comparing pre to post-training (Figure 2B).
not changed significantly (Figure 1A and B, respectively). Neither ACCβ total protein expression nor Ser221-ACCβ
phosphorylation changed with the exercise intervention
(Figure 2C). Moreover, 24 weeks of stationary cycle aerobic
3.4 | Muscle glucose metabolism
interval training did not alter the basal expression of total and
Participants muscle glycogen content remained unaltered phosphorylated Thr286-CamKII levels (Figure 2D).
after 6 months of AIT (223±58 vs 263±75 mmol·mg−1 dry
muscle). Similarly, total protein expression of HKII was sim-
3.6 | Muscle lipases
ilar after the intervention (Figure 2E). However, the total pro-
tein amount of the glucose transporter GLUT4 was increased EL expression showed a significant increase (33.3%±0.4%;
by 20.5% (P<.05; Cohen’s d=0.52; Figure 2F). Figure 3A; P<.05; Cohen’s d=0.85) after training compared
to baseline values, with no differences in the HSL and LPL
protein levels (Figure 3B-C).
3.5 | Basal skeletal muscle Thr172-AMPKa/
Ser221-ACCβ and Thr286-CaMKII levels
Total AMPKα protein expression was a 23.4% higher after the 4 | DISCUSSION
intervention compared to pre-training levels (P<.05; Cohen’s
d=0.57; Figure 2A). The Thr172AMPKα/Total AMPKα The current study reveals that long-term (24 weeks) aerobic
(fractional phosphorylation of AMPKα) was not statistically interval training induces a number of health benefits related
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590 GUADALUPE-GRAU et al.
F I G U R E 3 Muscle lipase expression before (PRE) and after (POST) 6 mo of AIT. (A) endothelial lipase expression (EL); (B) hormone-
sensitive lipase expression (HSL) and (C) lipoprotein lipase expression (LPL). Solid lines represent individual values for each participant.
*Significantly higher from pre-training (P<.05)
training, because MetS patients experience the habitual cardio- There is, to our knowledge, no data about the effects of long-
vascular adaptations that improve oxygen kinetics in healthy term intermittent perturbations of the cellular energy state (eg,
subjects.38 It is somehow surprising the significant but small 24-week interval cycling exercise training) in the skeletal mus-
effect that the training intervention exerted on the aerobic ca- cle cellular signals and enzymatic adaptation of MetS patients.
pacity of our subjects (ie, 8.0% increase in VO2peak), in com- We observed that this training increases total AMPKα protein
parison with other studies performed on MetS patients were level (Figure 2A). Nielsen and colleagues demonstrated an
they observed around a 35% increase in VO2peak.16 Among 85% higher level of total AMPKα protein content in endurance
the possible causes for this low responsiveness is the fact that trained vs sedentary healthy subjects.45 Moreover, 8 weeks of
the subjects recruited for this study participated in a previous strength training induced a significant increase in total AMPKα
4 months AIT study performed by our research group,9 where in MetS patients.46 We observed a 20% higher total AMPKα
they showed a mean increase in VO2peak of 21%. Another expla- protein levels after the training intervention, suggesting that an
nation could be that the selected training intervention may not increase in total AMPK protein content is an early event occur-
be the best therapeutic exercise training regime for longer than ring in the adaptation of MetS skeletal muscle toward a more
4 months studies, and additional volume and/or intensities are oxidative muscle phenotype. It remains unknown what training
required to increase aerobic capacity. On the other hand, there program intensity, volume, and duration would exert the best
is a positive relationship between the relative change in VO2max adaptations in MetS individuals, although the metabolic fluc-
in response to physical training and CS activity (as a surro- tuations induced by intermittent exercise appear to be a potent
gate of mitochondrial biogenesis).39 Our participants increased stimulus for PGC-1α upstream kinases such as AMPK.
their VO2peak by 8.0%, accompanied by a 26.0% increase in Regarding calcium- mediated muscle signaling, existing
CS activity (Pearson correlation r=.63; P<.05). Therefore, it literature states that acute high-intensity exercise is able to in-
seems that AIT-induced improvements in VO2peak are coupled duce Thr286-CaMKII activation,20,47 and short term (3 weeks)
to mitochondrial biogenesis in MetS patients. PGC-1α mRNA of one-legged endurance exercise training provokes a onefold
expression is also frequently used as a marker of mitochon- increase in maximal CaMKII activity and CaMKII kinase iso-
drial biogenesis, due its action as coactivator of transcription form expression in young healthy men.48 Conversely, the rest-
factors, and nuclear and mitochondrial genes required for the ing skeletal muscle levels of either pThr286-CaMKII or total
organelle’s synthesis.40 PGC-1α expression and activity are CaMKII remained unchanged in the present investigation. The
regulated by upstream signaling pathways of protein kinases, as lack of available data about long-term adaptations on CaMKII
AMPK and CaMKII.23,41 We have observed that basal pThr172- signaling pathway in MetS individuals and the different exer-
AMPKα fractional phosphorylation did not change with the cise protocols applied make comparisons difficult, and further
training intervention, maybe because muscle samples were studies on the effects of AIT on MetS regarding calcium-
taken in resting conditions where there is lack of an increased mediated muscle signaling are therefore warranted.
energy demand (ie, reduced ATP:AMP ratio) that would stimu-
late AMPK activation. In support for our results, other authors
4.2 | Changes in muscle fat metabolism
have shown similar basal pThr172-AMPKα phosphorylation
markers (β-hydroxyacyl-CoA-dehydrogenase,
levels in muscle biopsies obtained from resting vastus lateralis
EL, ACC) and maximal fat oxidation induced
muscle of obese and lean subjects. 42,43 Furthermore, Kjøbsted
by exercise
et al.44 have recently reported an intact regulation of the AMPK
signaling network in response to acute exercise in skeletal mus- Our data support the classical metabolic adaptations to aero-
cle of male patients with type 2 diabetes. bic exercise training that increase the reliance on fat as energy
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592 GUADALUPE-GRAU et al.
substrate during exercise,49 confirmed by a significant 36% investigation. Consequently, more mechanistically driven
increase in maximal fat oxidation capacity in our patients. studies (ie, combining in vivo protein activity and function
At the muscle cell level, activation of AMPK phosphorylates and ex vivo mitochondrial FAO respiration) are needed to
and inhibits acetyl-coenzyme A carboxylase (ACC), lead- elucidate the physiological role of EL in human skeletal
ing to reduced malonyl-coenzyme A and increased FA flux muscle. Moreover, although we inspected our muscle sam-
into the mitochondria via carnitine palmitoyl transferase-1.50 ples under the microscope to remove any visible blood, fat,
ACC phosphorylation is therefore considered a marker of in- or connective tissue, it is not possible to ensure that the EL
creased FA oxidation in the muscle. In concordance with the expression detected in the blots is all from myocyte tissue.
abovementioned lack of changes in the degree of pThr172-
AMPKα levels, pSer221- ACCβ remained unchanged after
4.3 | Changes in muscle carbohydrate
24 weeks of AIT. Moreover, the independent index of mito-
metabolism muscle markers (HK, GLUT4,
chondrial fatty acid β-oxidation, this is, hydroxy-acyl-CoA-
glycogen) and insulin sensitivity (CSi, HOMA-
dehydrogenase enzymatic activity confirmed the lack of
IR, blood glucose)
adaptation at the resting state. Our results imply that in meta-
bolic syndrome patients, the increase in the maximal capacity Most of the studies analyzing insulin sensitivity responses to
to oxidize fat during exercise is not explained by an increase AIT report small or no changes on steady state glucose infu-
in resting mitochondrial FA oxidation capacity or basal acti- sion rate during an euglycemic clamp,15 oral glucose toler-
vation of key proteins governing skeletal muscle metabolic ance tests, and insulin sensitivity indexes.9,13,38 Accordingly,
regulation (AMPK-ACC). It can be alternatively explained the data included in this report (lack of changes in Csi,
by an increased oxygen carrying and delivery capacity of HbA1c, HOMA-IR, and fasting blood glucose concentration)
the blood,51 or increased capacity of FA uptake or release suggest that 24 weeks of increasing intensity AIT alone is
from the lipid droplets for oxidation. We acknowledge that largely futile at decreasing insulin resistance at the whole-
phosphorylation of AMPK-ACC in response to acute exer- body level and that additional interventions (ie, diet or medi-
cise after a training intervention could result in substantial cine) are necessary to increase insulin sensitivity in metabolic
changes in the degree of pThr172-AMPKα and pSer221-ACCβ syndrome patients. This lack of adaptation was also reflected
levels, and such adaptations could also influence the results at the muscle level, where glycogen content and HKII, a key
presented in the study. We made a large effort to obtain mus- protein in the regulation of glucose metabolism remained
cle biopsies before and after the training intervention, but a unchanged. Interestingly, we observed a 20.5% increase in
limitation is the lack of acute post-exercise muscle biopsies. the intramuscular levels of the glucose transporter GLUT4,
Eight weeks endurance training in obese subjects in- suggesting that discrete adaptations at the cellular level occur
creases the activity of lipases involved in the intramuscular before a visible change in whole-body insulin sensitivity can
lipolysis regulation, as HSL and ATGL, but not total HSL be observed.
protein content,52 and 2 weeks physical inactivity (induced
by leg immobilization) and age negatively affect intramus-
4.4 | Metabolic syndrome factors are not
cular lipolytic capacity in men, leading to intramuscular tri-
further reduced with 24 weeks of AIT
glycerides accumulation.25 In agreement, we observed no
differences in total HSL and LPL protein content with train- We have previously reported that in sedentary MetS pa-
ing, although of novelty, we observed higher protein amount tients 16 weeks of an AIT program could reverse metabolic
of EL with 24 weeks AIT in our MetS patients. This lipase syndrome factors in roughly one-third of this population
encoded by the LIPG gene and synthesized by endothelial despite the absence of a diet intervention. In the present in-
cells was initially reported not to be expressed in skeletal vestigation, a 27.3% of the participants reversed metabolic
muscle53; however, a recent study suggests a possible role for syndrome factors <3. The most important changes were
EL in endothelial tissue of human skeletal muscle. Vigelsø observed in blood pressure (12% decrease), blood HDL-c
et al. showed a 100% higher EL expression in endurance concentrations (12% increase), and to a lower extent in
trained compared to healthy middle-aged men and suggested waist circumference (3.8%). However, plasma glucose and
that EL might be an alternative pathway for FA uptake in triglycerides concentrations were not significantly reduced.9
skeletal muscle.25,26 This EL increase can also be explained The question raised from this investigation was whether an
by a higher microvascular density with endurance training, AIT program with a longer duration could be more adequate
which has also been observed after sprint interval training in to revert the remaining MetS components to normal clini-
previously sedentary males.54 Although we found a higher cal values. Surprisingly, we have observed that 24 weeks of
expression of muscle EL with aerobic interval training, this AIT significantly reduced blood pressure and waist circum-
was not coupled to an increased basal mitochondrial HAD ference to a similar extent (10.1 and 1.8%, respectively) than
activity and we did not measure angiogenesis in the present shorter duration AIT protocols,9,16,55,56 and tended to reduce
GUADALUPE-GRAU et al.
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