Low Anaerobic Threshold and Increased Skeletal Muscle Lactate
Production in Subjects with Huntington’s Disease
Andrea Ciammola, MD,1* Jenny Sassone, PhD,1 Monica Sciacco, MD,2 Niccolo` E. Mencacci, MD,1 Michela Ripolone, PhD,2
Caterina Bizzi, MD,3 Clarissa Colciago, PhD,1 Maurizio Moggio, MD,2 Gianfranco Parati, MD,3,4 Vincenzo Silani, MD,1
and Gabriella Malfatto, MD3
1Department of Neurology and Laboratory of Neuroscience, Centro ‘‘Dino Ferrari’’ Universita` degli Studi di Milano - IRCCS Istituto Auxologico
Italiano, Milan, Italy
2Department of Neurological Sciences, Centro ‘‘Dino Ferrari,’’ Universita` di Milano, IRCCS Fondazione Ospedale Maggiore Policlinico,
Mangiagalli and Regina Elena, Milan, Italy
3Department of Cardiology, S. Luca Hospital, IRCCS Istituto Auxologico Italiano, Milan, Italy
4Department of Clinical Medicine and Prevention, Universita` di Milano-Bicocca, Milan, Italy
ABSTRACT: Mitochondrial defects that affect cel-
lular energy metabolism have long been implicated in the
etiology of Huntington’s disease (HD). Indeed, several
studies have found defects in the mitochondrial functions
of the central nervous system and peripheral tissues of
HD patients. In this study, we investigated the in vivo oxi-
dative metabolism of exercising muscle in HD patients.
Ventilatory and cardiometabolic parameters and plasma
lactate concentrations were monitored during incremen-
tal cardiopulmonary exercise in twenty-ﬁve HD subjects
and twenty-ﬁve healthy subjects. The total exercise
capacity was normal in HD subjects but notably the HD
patients and presymptomatic mutation carriers had a
lower anaerobic threshold than the control subjects. The
low anaerobic threshold of HD patients was associated
with an increase in the concentration of plasma lactate.
We also analyzed in vitro muscular cell cultures and
found that HD cells produce more lactate than the cells
of healthy subjects. Finally, we analyzed skeletal muscle
samples by electron microscopy and we observed strik-
ing mitochondrial structural abnormalities in two out of
seven HD subjects. Our ﬁndings conﬁrm mitochondrial
abnormalities in HD patients’ skeletal muscle and sug-
gest that the mitochondrial dysfunction is reﬂected func-
tionally in a low anaerobic threshold and an increased
lactate
synthesis
during
intense
physical
exercise.
V
C 2010 Movement Disorder Society
Key Words: Huntington’s disease; skeletal muscle;
anaerobic threshold; mitochondria
Huntington’s disease is an autosomal-dominant neu-
rodegenerative disorder characterized by chorea, de-
mentia,
and
psychiatric
disturbances.
The
genetic
mutation underlying the disease is the expansion of
the triplet cytosine-adenosine-guanosine (CAG) in the
IT-15 gene; this mutation encodes for an expanded
polyglutamine (polyQ) tract in the huntingtin (htt) pro-
tein.1 Htt is ubiquitously expressed in the brain as well
as in many extra-CNS tissues such as skeletal muscle.2
The expression of mutated htt has deleterious effects on
skeletal muscle; in particular, HD patients suffer from
muscular weakness3,4 and undergo progressive muscular
wasting.5,6 In addition to this clinical evidence, various
abnormalities have been observed in the muscular tissues
of HD patients and in HD mouse models. These abnor-
malities include skeletal muscle atrophy7,8 and impair-
ment of adenosine triphosphate (ATP) metabolism,
which manifests as a reduced ratio of phosphocreatine to
------------------------------------------------------------
Additional Supporting Information may be found in the online version of
this article.
*Correspondence to: Andrea Ciammola, MD, Department of Neurology
and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, via
Spagnoletto 3, 20149 Milan, Italy; a.ciammola@auxologico.it
Funding agencies: This work was supported in part by Italian Health
Ministry (AC, Malattie Neurodegenerative ex art. 56 legge ﬁnanziaria
2004), and by Associazione Amici del Centro Dino Ferrari, University of
Milan, the Telethon project GTB07001, the Eurobiobank project QLTR-
2001-02769 and R.F. 02.187 Criobanca Automatizzata di Materiale
Biologico.
Relevant conﬂict of interest: Nothing to report.
Full ﬁnancial disclosures and author roles may be found in the online
version of this article.
Received: 30 March 2010; Revised: 22 April 2010; Accepted: 26 April
2010
Published online 7 October 2010 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.23258
R E S E A R C H
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Movement Disorders, Vol. 26, No. 1, 2011
inorganic phosphate and a lower production of mito-
chondrial ATP.9–11 Whereas mitochondria-related ener-
getic dysfunctions have been found in both the CNS and
skeletal muscle of HD patients,12 it is still unclear
whether the cellular energy metabolism impairment is a
primary event in the cascade of pathogenic events that
occurs in the brains of HD patients. To clarify this issue,
previous studies used magnetic resonance spectroscopy
(MRS) to analyze the brain lactate levels of symptomatic
and presymptomatic HD subjects; these studies, how-
ever, produced conﬂicting data.13–16 As skeletal muscle
cells, like neurons, are postmitotic cells that are highly
dependent on oxidative metabolism, we decided to inves-
tigate the in vivo oxidative metabolism of exercising
muscle in HD subjects. We hypothesized that during
physical exercise, the lower level of ATP synthesis in HD
patients would reduce the ability of muscle cells to
extract O2 from blood; as a result, HD patients would
reach the anaerobic threshold (AT) early and show a cor-
respondingly high level of lactate production.17,18 This
clinical study is designed to measure ventilatory and car-
diometabolic parameters as well as lactate production in
presymptomatic and symptomatic HD gene carriers dur-
ing a cardiopulmonary exercise test.
Patients and Methods
HD Patients, Presymptomatic HD Subjects,
and Control Subjects
Table 1 shows the clinical and demographic data of
the HD patients and control subjects. All of the HD
subjects had had DNA analysis demonstrating more
than 39 CAG repeats. Patients were excluded if they
met any of the following criteria: (1) concomitant pres-
ence of metabolic, endocrine or muscular disorders; (2)
arterial hypertension that required treatment (deﬁned as
a systolic pressure >140 mm Hg and a diastolic pres-
sure >90 mm Hg); (3) systolic and/or diastolic heart
failure (deﬁned as an ejection fraction <50% and/or an
abnormal diastolic phase) and valvular or morphologi-
cal abnormalities diagnosed through echocardiography;
(4) use of drugs that affect metabolism and/or muscular
functions;(5) a history of drug addiction (6) a body
mass index (BMI) <18 or >25 and (7) an inability to
use the bicycle ergometer. All HD patients were able to
walk without assistance and able to independently
carry out activities of daily living.
Controls were selected from healthy volunteer sub-
jects according to the same exclusion criteria. Mean
age of the control group did not signiﬁcantly differ
from mean age of presymptomatic and symptomatic
HD group. Mean age of presymptomatic group was
lower as compared to symptomatic HD group (P <
0.05). Presymptomatic-HD and control groups both
included subjects that had a sedentary life style and
subjects that performed moderate physical activity (1–
2 hours physical exercise/week).
Each subject gave his or her written consent after
being fully informed of any risks and discomfort asso-
ciated with participation in the study. The study was
approved by the Ethics Committee of the Istituto Aux-
ologico Italiano, and all study procedures followed the
recommendations of the Helsinki Declaration of 1975.
Exercise Protocol
All subjects rested for 45 minutes before beginning
the exercise portion of the study. The exercise test was
performed on an electrically-braked bicycle according
to a validated protocol.19 A cardiopulmonary exercise
system (Sensor Medics V2900, USA) was used to mon-
itor breath-by-breath measurements of VE (expired
ventilation), VO2 and VCO2. Derived entities such as
VE for O2 and CO2 (VE/VO2, VE/VCO2), the respira-
tory quotient VCO2/VO2 and respiratory rate per mi-
nute
were
presented
on-line.
The
equipment
was
calibrated before every test. A 12-lead ECG was used to
monitor for arrhythmia and ST segment changes. The
test began with 2 minutes of variable sampling whereas
the subject was at rest and was followed by 2 minutes
of unrestricted exercise. The workload was increased by
25 Watts every 2 minutes. The exercise test was symp-
tom-limited and used a Borg scale (from 0 to 10) to
rate dyspnoea, fatigue and chest pain. The subjects were
TABLE 1. Demographic, clinical, and genetic data of HD patients (nine males and six females), presymptomatic
subjects (seven males and three females), and healthy controls (16 males and nine females)
Symptomatic HD
patients (N ¼ 15)
Presymptomatic HD
subjects (N ¼ 10)
Controls (N ¼ 25)
Age (yr)
48.2 6 10.2 (29–67)
37.6 6 6.7 (21–45)
43.7 6 10.6 (31–70 )
CAG triplet number
45.3 6 3.2 (41–52)
43.8 6 2.5 (42–49)
–
Age at onset (yr)
44.7 6 10.9 (28–65)
–
–
Duration of illness (yr)
3.9 6 3.1 (1–10)
–
–
UHDRS part I
31.0 6 12.2 (17–53)
–
–
Total functional capacity
10.7 6 2.2 (6–13)
–
–
Data are expressed as mean 6 SD (range).
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encouraged to exercise until they were exhausted. Blood
pressure and heart rate were measured every 2 minutes.
All respiratory parameters were measured from plots
over time, resulting in moving average values. The peak
VO2, VE/VO2, and VE/VCO2 were the last of three val-
ues that were recorded during the ﬁnal 30 seconds of
exercise. If this last value was not the highest, the mean
of the last three values was calculated. The anaerobic
threshold was calculated according to the V-slope
method. After the test, patients rested in a supine posi-
tion for at least 5 minutes. The following exercise pa-
rameters were evaluated in all subjects:
1. Exercise/cardiac parameters:
(a) Maximal
ergometric
working
capacity
(Wpeak), deﬁned as the maximal work
(Watts) reached for at least 1 minute
(b) Peak exercise heart rate (HRpeak) and
heart rate at the anaerobic threshold (HR
AT)
(c) Peak VO2/kg (mL/Kg/min), i.e., the maxi-
mal oxygen consumption, expressed both
in absolute values (ml/Kg/min) and as a
percent of theoretical maximum capacity
according to age, body type, and sex (peak
VO2 %)
(d) O2
pulse
(ml/beat)
both
at
anaerobic
threshold (AT pO2) and at the exercise
peak (peak pO2)
(e) Aerobic threshold (AT VO2), expressed as
an absolute value (ml/Kg/min), as a percent
of the predicted maximum (AT%) and as
Watts reached (AT Watts)
2. Ventilatory variables:
(a) Respiratory
quotient
at
the
anaerobic
threshold (RQ AT) and at peak exercise
(RQ peak)
(b) Ratio of dead space to tidal volume (VD/
Vt)
(c) Ratio of ventilation to CO2 production at
peak exercise (peak VE/VCO2)
Blood Sampling and Lactate Concentration
Assay
A peripheral antecubital venous access was posi-
tioned before the beginning of the test. Blood samples
were drawn whereas the subject was at rest and at the
beginning of each 2-minute incremental step during
the exercise. The lactate concentration of the plasma
was assessed using a colorimetric assay (Lactate Rea-
gent, Trinity Biotech, Ireland).
Muscle Biopsies
Informed consent was obtained from each patient.
Open muscle biopsies were obtained at rest from the
biceps brachii muscle of patients through a small sur-
gical incision under local anesthesia.
Human Muscular Cultures
Human myoblast cultures were obtained from bi-
opsy specimens (supporting information Table 1) as
previously described.20 Equal numbers of myoblasts
were plated on 100-mm dishes in 10 ml of culture me-
dium. The media and cells were collected 24 hours
later. The media were assayed for lactate concentra-
tion and the cells were counted using Coulter Counter
cell (Beckman, CA).
Morphological Studies
We examined skeletal muscle biopsies from seven
HD patients. For light microscopy studies, cryostat
cross sections were processed according to standard
histological (Gomori’s Trichrome, H&E) and histo-
chemical (COX, SDH, double staining for COX, and
SDH) techniques.21 A small part of each bioptic sam-
ple was ﬁxed in 2,5% glutaraldehyde (pH 7,4), post-
ﬁxed in 2% osmium tetroxide and then embedded in
Spurr’s resin for ultrastructural examination. Finally,
ultrathin sections were stained with lead citrate and
uranyl acetate and examinated with Zeiss EM109
transmission electron microscope.21
Statistical Analysis
A Kolmogorov-Smirnov test was used to test the
data for normality and a Levene test was used to ver-
ify the homogeneity of group variances. Cardiopulmo-
nary
parameters
and blood lactate
concentrations
were compared with an analysis of variance (ANOVA)
procedure using a Tukey test. Pearson or Spearman
correlation coefﬁcients were used to test for correla-
tions between clinical and genetic data and the cardio-
pulmonary
parameters.
Lactate
concentrations
in
myoblast culture media were compared with a Krus-
kal-Wallis ANOVA followed by Dunn’s test.
Results
Cardiorespiratory Measurements
All of the subjects completed the exercise test with-
out complications. In all subjects, the peak RQ was
close to 1, showing a truly maximal test. No arrhyth-
mias or ST changes suggestive of ischemic problems
were detected in HD or control subjects during the
exercise. The cardiopulmonary test parameters of HD
patients, presymptomatic HD subjects and healthy
controls are reported in Table 2.
The peak power (Wpeak) and peak oxygen con-
sumption (peak VO2) values were signiﬁcantly reduced
in symptomatic HD patients as compared to controls
(Table
2,
Fig.
1A,B).
No
difference
in
maximal
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Movement Disorders, Vol. 26, No. 1, 2011
exercise capacity was detected between presympto-
matic HD and control subjects. Notably, there was no
difference in O2 peak pulse, VD/Vt or VE/VCO2
among the groups; this data indicates a normal cardiac
and ventilatory performance in all the groups.22
The anaerobic threshold values were signiﬁcantly
lower in the symptomatic and presymptomatic HD sub-
jects than in the control subjects; this was true for all
measurements, including the absolute value (ATVO2,
mL/Kg/min), percent of the predicted maximum (AT%)
and Watts reached (AT, Watt) (Table 2, Fig. 1C–E). We
examined the data for a potential correlation between
the cardiopulmonary test parameters and clinical or
genetic data of the HD subjects. In the symptomatic HD
patients, no signiﬁcant correlation was found among
clinical data (age at onset, duration of illness, UHDRS I,
and TFC), genetic data (CAG repeat number), and
Wpeak, ATVO2, AT%, or AT. Notably, a signiﬁcant
negative correlation was found between AT% and CAG
repeat number in presymptomatic HD subjects (Fig. 1F;
P < 0.0001; R ¼ 0.873, Spearman Correlation).
Blood Lactate Accumulation During a
Cycloergometric Test and Lactate Production
from In Vitro Muscular Cell Cultures
Figure 2A shows mean values of blood lactate con-
centrations at the various levels of work. The plasma
lactate values did not differ between the symptomatic
HD patients and the control subjects when they were
at rest; however, at 50 and 75 Watts the mean plasma
lactate concentration was signiﬁcantly higher in symp-
tomatic HD patients than in the controls (50 Watts, P
¼ 0.021 vs controls; 75 Watts, P ¼ 0.014 vs controls).
Presymptomatic HD subjects had a mean lactate value
at 50 Watts that was higher than that of the controls,
but the difference was not statistically signiﬁcant.
To determine whether the increased lactate produc-
tion was related to a primary defect in the mitochon-
drial function of muscular cells, we measured lactate
production in in vitro muscular cell cultures from ﬁve
HD patients and ﬁve age-matched controls (the biopsy
data are reported in supplemental Table 1). The lac-
tate concentration in the media of the HD cultures
was signiﬁcantly higher than in the media of the con-
trol cultures (Fig. 2B).
Histochemistry and Ultrastructural Studies of
HD Skeletal Muscle
We examined six out of seven muscle biopsies (sam-
ple n 3 was too small for reliable examination, Fig.
3A) and we found small groups of type II ﬁbers in
patients 1, 5, 6, and 7, patient n 1 also presenting
scattered type II hypotrophic ﬁbers. We detected no
signiﬁcant oxidative alterations except for the presence
of 1–2 COX-negative ﬁbers, without mitochondrial
proliferation (normal SDH), in patients n 1, 6, and 7.
In two patients (n 3 and 5), ultrastructural studies
showed a consistent number of abnormally elongated
mitochondria
with
derangement
of
cristae
and
vacuoles (Fig. 3B,C). Also, some mitochondria gradu-
ally become swollen with progressive loss of matrix
substance
and disruption
of residual
cristae (Fig.
3D,E).
Discussion
Our study shows that symptomatic HD subjects
have a reduced work capacity (Wpeak) during a car-
diopulmonary test. This data complements the recent
reported of a signiﬁcant reduction in muscle strength
in symptomatic HD patients.4 Presymptomatic HD
subjects had normal Wpeak values during the same
exercise test, which suggests that the Wpeak reduction
TABLE 2. Cardiopulmonary test parameters of HD patients, presymptomatic HD subjects, and healthy controls
Symptomatic HD patients
Presymptomatic HD subjects
Controls
Wpeak (Watts)
111.7 6 37.6; (75–200)
165.0 6 39.4; (125–225)
158.7 6 45.8; (100–250)
P ¼ 0.003 s-HD vs C
Peak VO2/kg (mL/Kg/min)
23.4 6 6.7; (14.4–39.1)
29.5 6 7.0; (19.6–42.2)
28.8 6 6.0; (19.7–47.5)
P ¼ 0.026 s-HD vs C
Peak VO2/kg (% of theorethical)
75.7 6 22.3; (42–125)
78.7 6 21.1; (53–113)
83.3 6 14.7; (60–129)
Heart rate peak (beats/min)
145.6 6 19.4; (106–180)
156.3 6 11.0; (139–176)
154.3 6 18.9; (112–185)
RQ (peak) adimensional ratio
1.0 6 0.1; (1.0–1.1)
1.1 6 0.1; (0.9–1.3)
1.1 6 0.2; (0.9–1.7)
O2 pulse peak (mL/beat)
11.3 6 4.2; (5.8–20.4)
13.5 6 3.7; (8.2–18.3)
13.4 6 3.5; (6.9–18.8)
O2 pulse peak (%)
84.5 6 19.7; (49–128)
93.1 6 19.0; (73–135)
100.0 6 21.6; (62–140)
VD/VT (%)
97.3 6 36.5; (57–187)
72.6 6 17.6; (40–92)
66.5 6 19.4; (30–104)
VE/VCO2 adimensional ratio
32.0 6 2.9; (27–36)
30.1 6 4.3; (24–38)
29.9 6 3.2; (26–36)
AT VO2 (mL/Kg/min)
13.3 6 2.5; (9.7–19.0)
13.6 6 3.3; (9.8–20.3)
19.0 6 5.0; (11.9–33.1)
P ¼ 0.000125 s-HD vs C
P ¼ 0.000125 preHD vs C
AT (%)
38.9 6 7.3; (27–50)
35.3 6 8.0; (26–56)
54.7 6 13.1; (39–88)
P ¼ 0.000251 s-HD vs C
P ¼ 0.000166 preHD vs C
AT (Watts)
38.3 6 12.9; (25–50)
57.5 6 16.9; (25–75)
99.0 6 43.0; (50–200)
P ¼ 0.000002 s-HD vs C
P ¼ 0.000002 preHD vs C
Data are expressed as mean 6 SD; (range). Not reported statistical scores were P > 0.05.
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in symptomatic patients may be related to the reduc-
tion in muscle bulk that occurs as the disease pro-
gresses.5,6 Our ﬁndings conﬁrm a strength deﬁcit in
HD patients and support the idea that physical ther-
apy aimed at improving muscle strength could beneﬁt
these patients, particularly during the early stages of
the disease.23
This study shows that low anaerobic threshold (AT)
values and an early increase of blood lactate are
linked to HD. Both symptomatic and presymptomatic
HD subjects had an anticipated AT during the incre-
mental exercise. The AT is an index normally used to
estimate exercise capacity. During the initial (aerobic)
phase of cardiopulmonary exercise, expired ventilation
(VE) increases linearly with VO2 and reﬂects aerobi-
cally produced CO2 in the muscles. During the latter
phase of exercise, anaerobic metabolism occurs when
the oxygen supply cannot keep up with the increasing
FIG. 1. (A) Scatter plot of maximal ergometric working capacity values (Wpeak) and (B) maximal oxygen consumption, expressed as absolute val-
ues (Peak VO2) in HD patients (N 5 15), presymptomatic subjects (N 5 10) and control subjects (N 5 25). (C) Scatter plot of aerobic threshold val-
ues expressed as absolute value (ATVO2), (D) as percent of the predicted maximum (AT%) and (E) as Watts reached (AT Watts). Mean values are
indicated with horizontal bars. (F) Scatter plot graph showing that AT% correlates with CAG repeat number in presymptomatic HD subjects. The
graph shows nine dots because two subjects had identical AT% and CAG repeat number.
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Movement Disorders, Vol. 26, No. 1, 2011
metabolic requirements of exercising muscles. At this
time, there is a signiﬁcant increase in lactic acid pro-
duction in the muscles and in the blood lactate
concentration.24
In our opinion, the low AT values and elevation of
blood lactate in HD subjects reﬂect abnormalities in
O2 utilization; this is consistent with abnormal oxida-
tive metabolism in skeletal muscle. Presymptomatic
subjects did not show a reduction in Wpeak values,
which suggests that lower AT% values are not corre-
lated with muscular atrophy. Notably, our data high-
lighted an inverse correlation between AT% values
and CAG repeats in HD gene carriers; this data
strongly suggests that mutant htt directly results in
deﬁcits in the mitochondrial respiratory chain, even in
presymptomatic HD patients. Among symptomatic
HD patients, the CAG repeat number was not signiﬁ-
cantly correlated with AT% values. This data indi-
cates that factors other than the CAG repeat number
(such as muscular atrophy) may also contribute to
AT% reduction in the more advanced stages of the
disease. Several studies have suggested that the work
rate corresponding to the AT could be used as an
index for determining the optimal training intensity,25
therefore the information gathered in this study sug-
gests that a cardiopulmonary test should be included
in the physical therapy program for HD subjects.
Our examination of skeletal muscle tissue from six
HD subjects with an histochemical marker for mito-
chondrial oxidative function (COX) did not reveal any
signiﬁcant abnormalities in both presymptomatic and
symptomatic subjects. This data agrees with previously
reported histological and histochemical examination
of muscle biopsies from HD subjects.6 Given the pre-
viously reported observations of structural mitochon-
drial
abnormalities
in
cortical
biopsies
from
HD
patients26–28 and in the muscle biopsy from one HD
gene carrier,3 we performed electron microscopy ex-
amination of HD muscle biopsies. Interestingly, we
found abnormally elongated mitochondria with cristae
derangement and vacuoles in two specimens (pt n 3
and
5).
These
ﬁndings
are
similar
to
those
described.28,29 Pt n 3 is a 63-years-old woman with a
disease duration of 13 years and 42 CAG repeats,
whereas pt n 5 is a presymptomatic 36-years-old man
with 42 repeats. Interestingly, his father (pt n 6), who
has the same number of repeats and a disease duration
of 22 years, does not show structural mitochondrial
changes. We hypothesize that, as reported,28 the same
mitochondrial alterations could be present at central
nervous system level also in patients who do not show
skeletal muscle abnormalities. Also, a possible expla-
nation for the ﬁnding of mitochondrial alterations in
few subjects is that these alterations may correlate
with the lifestyle of the patients and may be more evi-
dent in physically active subjects than in more seden-
tary, possibly older, ones.
Conﬂicting data have been reported about cardiac
dysfunction in HD.12 Indeed, mutant htt has been
blamed
for
cardiotoxic
effects
in
mouse
models,
including heart atrophy7 and defects in contractile
functions.30 Nevertheless, epidemiological studies have
not found heart disease to be more common in HD
patients than in controls.31
In
this
study,
the
patients’
cardiopulmonary
response to exercise did not resemble the pattern that
is typical of patients with heart failure. At peak exer-
cise, the HD patients showed a normal O2 pulse,
which suggests a normal cardiac output22; in addition,
they had a normal ventilatory response, with VE/
VCO2 values below the cutoff-value of 35.32 These
results do not show an increased risk for cardiac dis-
ease in HD patients. Rather, the response of HD
patients to cardiopulmonary testing suggests a primary
defect in the muscular energetic metabolism. The
increased lactate production we found in HD myo-
blast cultures further highlights the inadequate mito-
chondrial oxidative respiration of HD muscle and
FIG. 2. (A) Lactate concentrations in blood (mean 6 SD) during car-
diopulmonary test (*P 5 0.021; **P 5 0.014 vs. controls). (B) Graph
representing the median and the percentiles of lactate concentrations
in cell culture media. Data were expressed as mg/dL and normalized
on cell number. The ends of the boxes define the 25th and 75th per-
centiles, with a line at the median and error bars defining the 10th and
90th percentiles. Medians were: HD cells 3.0 mg/dL/number of cells.
Control cells: 1.6 mg/dL/number of cells (P 5 0.003 vs. control cells).
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agrees with our previous reports showing mitochon-
drial dysfunction in HD myoblasts.20,33
Finally, we believe that AT measures could be useful
as in vivo assays during
the screening of drugs
designed to improve mitochondrial function in HD
patients. For example, a deﬁcit in PGC-1a (peroxi-
some proliferator-activated receptor-c coactivator 1a),
a transcriptional coactivator implicated in mitochon-
drial biogenesis,
was recently found in both the
brain34 and skeletal muscles35 of HD patients. Mole-
cules that activate PGC-1a may be therapeutically use-
ful,36 and in vivo AT measures in HD subjects could
help to evaluate a potential drug’s beneﬁts.
Acknowledgments:
The authors wish to thank the patients and their
families (Associazione Mauro Emolo O.N.L.U.S.) for their precious sup-
port. We thank Dr.ssa Cinzia Tiloca for her technical support.
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H U N T I N G T O N ’ S
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Low anaerobic threshold and increased skeletal muscle lactate production in subjects with Huntington's disease.
Ciammola, Andrea,Sassone, Jenny,Sciacco, Monica,Mencacci, Niccolò E,Ripolone, Michela,Bizzi, Caterina,Colciago, Clarissa,Moggio, Maurizio,Parati, Gianfranco,Silani, Vincenzo,Malfatto, Gabriella