Skeletal muscle pathology in Huntington's disease

Abstract

Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by the expansion of a polyglutamine stretch within the huntingtin protein (HTT). The neurological symptoms, that involve motor, cognitive and psychiatric disturbances, are caused by neurodegeneration that is particularly widespread in the basal ganglia and cereberal cortex. HTT is ubiquitously expressed and in recent years it has become apparent that HD patients experience a wide array of peripheral organ dysfunction including severe metabolic phenotype, weight loss, HD-related cardiomyopathy and skeletal muscle wasting. Although skeletal muscles pathology became a hallmark of HD, the mechanisms underlying muscular atrophy in this disorder are unknown. Skeletal muscles account for approximately 40% of body mass and are highly adaptive to physiological and pathological conditions that may result in muscle hypertrophy (due to increased mechanical load) or atrophy (inactivity, chronic disease states). The atrophy is caused by degeneration of myofibers and their replacement by fibrotic tissue is the major pathological feature in many genetic muscle disorders. Under normal physiological conditions the muscle function is orchestrated by a network of intrinsic hypertrophic and atrophic signals linked to the functional properties of the motor units that are likely to be imbalanced in HD. In this article, we highlight the emerging field of research with particular focus on the recent studies of the skeletal muscle pathology and the identification of new disease-modifying treatments.

Full text

MINI REVIEW ARTICLE
published: 06 October 2014
doi: 10.3389/fphys.2014.00380
Skeletal muscle pathology in Huntington’s disease
Daniel Zielonka1*, Izabela Piotrowska2, Jerzy T. Marcinkowski1and Michal Mielcarek3*
1Department of Social Medicine, Poznan University of Medical Sciences, Poznan, Poland
2MRC National Institute for Medical Research, London, UK
3Department of Medical and Molecular Genetics, King’s College London, London, UK
Edited by:
Julio L. Vergara, University of
California, Los Angeles, USA
Reviewed by:
Seth L. Robia, Loyola University
Chicago, USA
Andrew Alvin Voss, Wright State
University, USA
*Correspondence:
Daniel Zielonka, Department of
Social Medicine, Poznan University
of Medical Sciences, Rokietnicka
Str., No. 5 “C,” 60-806 Poznan,
Poland
Michal Mielcarek, Department of
Medical and Molecular Genetics,
School of Medicine, King’s College
London, 8th Floor Tower Wing,
Guy’s Hospital Great Maze Pond,
London, SE1 9RT, UK
e-mail: michal.mielcarek@kcl.ac.uk
Huntington’s disease (HD) is a hereditary neurodegenerative disorder caused by the
expansion of a polyglutamine stretch within the huntingtin protein (HTT). The neurological
symptoms, that involve motor, cognitive and psychiatric disturbances, are caused by
neurodegeneration that is particularly widespread in the basal ganglia and cereberal
cortex. HTT is ubiquitously expressed and in recent years it has become apparent
that HD patients experience a wide array of peripheral organ dysfunction including
severe metabolic phenotype, weight loss, HD-related cardiomyopathy and skeletal muscle
wasting. Although skeletal muscles pathology became a hallmark of HD, the mechanisms
underlying muscular atrophy in this disorder are unknown. Skeletal muscles account for
approximately 40% of body mass and are highly adaptive to physiological and pathological
conditions that may result in muscle hypertrophy (due to increased mechanical load) or
atrophy (inactivity, chronic disease states). The atrophy is caused by degeneration of
myofibers and their replacement by fibrotic tissue is the major pathological feature in many
genetic muscle disorders. Under normal physiological conditions the muscle function is
orchestrated by a network of intrinsic hypertrophic and atrophic signals linked to the
functional properties of the motor units that are likely to be imbalanced in HD. In this
article, we highlight the emerging field of research with particular focus on the recent
studies of the skeletal muscle pathology and the identification of new disease-modifying
treatments.
Keywords: Huntington’s disease, peripheral pathology, skeletal muscle atrophy, disease modifying treatment
INTRODUCTION
Huntington’s disease (HD) is neurodegenerative disorder caused
by the expansion of polyglutamine stretch within the huntingtin
protein (HTT) (Gusella et al., 1993; Vonsattel and DiFiglia, 1998;
Novak and Tabrizi, 2010). The disease is caused by the expan-
sion of a CAG repeat to over 35 CAG repeats in exon1 of the
huntingtin (HTT) gene which are normally observed in healthy
objects. Neurodegeneration, particularly widespread in the stri-
atal nuclei, basal ganglia and cereberal cortex, is a source of
neurological symptoms that involve motor, cognitive and psy-
chiatric disturbances (Novak and Tabrizi, 2010). This leads to
a wide-range of clinical features including personality changes,
motor impairment, dementia and weight loss that are likely to
progress over the course of 15–20 years to death (HDRG, 1993;
Walker, 2007). In mammals HTT is expressed in many tissues and
organs (Hoogeveen et al., 1993; Strong et al., 1993; Trottier et al.,
1995). HTT has been identified to be involved in many critical cel-
lular processes like transcription, protein trafficking and vesicle
transport (Li and Li, 2004). In mice HTT deletion is embryon-
ically lethal, leading to defects in all germ layers (Zeitlin et al.,
1995). It has been established that HTT is affecting organelles
and functional systems that are essential for all type cells i.e.,
mitochondria, ubuquitin-proteasome system and this phenom-
ena is not tissue specific (Li and Li, 2004; Sassone et al., 2009;
van der Burg et al., 2009; Zielonka et al., 2014). A recent study
of the heart function in two HD mouse models identified pro-
nounced contractile heart dysfunction, which might be a part of
dilatated cardiomyopathy (DCM). This was accompanied by the
re-expression of fetal genes, apoptotic cardiomyocyte loss and a
moderate degree of interstitial fibrosis (Mielcarek et al., 2014).
Therefore it is likely that the peripheral pathology of HD, such
as weight loss and severe skeletal muscle atrophy, might have a
significant input to the disease progression.
SKELETAL MUSCLE PATHOLOGY IN HD PATIENTS
A case-study report showed that a semi-professional marathon
runner (43 CAGs) developed signs of a slowly progressing myopa-
thy with elevated creatine kinase levels many years before first
signs of chorea were detected. Muscle biopsy revealed a mild
myopathy with mitochondrial pathology including a complex IV
deficiency (Kosinski et al., 2007). The isometric muscle strength
of 6 lower limb muscle groups was measured in 20 people with
HD and matched healthy controls. HD patients had reduced mus-
cle strength by 50% on average in comparison to healthy matched
controls (Busse et al., 2008). Several studies have reported defects
in the mitochondrial function of the central nervous system and
skeletal muscles in HD patients (Reddy, 2014). For example,
the non-invasive method of 31P-MRS (31P- Magnetic Resonance
Spectroscopy) showed a reduced phosphocreatine to inorganic
phosphate ratio in the symptomatic HD patients at rest. Muscle
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e-mail: daniel.zielonka@gmail.com;

Zielonka et al. Atrophy of skeletal muscles in HD
ATP/phosphocreatine and inorganic phosphate levels were signif-
icantly reduced in both symptomatic and presymptomatic HD
subjects (Lodi et al., 2000). During recovery from exercise, the
maximum rate of mitochondrial ATP production was reduced
by 44% in the symptomatic HD patients and by 35% in the
presymptomatic HD carriers. HD subjects showed also a deficit
in the mitochondrial oxidative metabolism and that might sup-
port a role for mitochondrial dysfunction as a key factor involved
in the HD-related muscle pathogenesis (Lodi et al., 2000; Saft
et al., 2005). In addition, the total exercise capacity was normal
in HD subjects but notably the presymptomatic HD patients had
a lower anaerobic threshold and increased level of plasma lactate
(Ciammola et al., 2011). In vitro muscle cell cultures revealed that
HD cells produced more lactate and that might be indicative of
a higher glycolysis level (Ciammola et al., 2011). Furthermore,
muscle cultures showed cellular abnormalities including mito-
chondrial membrane potential, cytochrome c release, increased
CASPASE-3, −8, and −9 levels and defective cell differentiation,
likely due to the formation of HTT inclusions in differentiated
myotubes (Ciammola et al., 2006). Finally, electron microscopy
showed striking mitochondrial defects like abnormally elon-
gated and swollen mitochondria with derangement of cristae and
vacuoles (Ciammola et al., 2011).
ON THE WAY TO UNDERSTAND MUSCLE PATHOLOGY IN
HD—AN ANIMAL MODEL
Recent years of research on HD pathogenesis resulted in a gen-
eration of many HD transgenic mouse models including mHTT
N-terminal fragments and full-length murine or human mHTT
(Crook and Housman, 2011; Lee et al., 2013; Rattray et al., 2013).
R6/2 mice are transgenic for a mutated N-terminal exon 1 HTT
fragment and are the most frequently used in pre-clinical settings.
Behaviorally, R6/2 animals at first display a spatial learning deficit
at 3–4 weeks of age (Lione et al., 1999). Attention learning deficits
and abnormal performance in motor tests (swimming and high
speed rotarod) appear at 5–6 weeks of age (Carter et al., 1999;
Lione et al., 1999; Murphy et al., 2000), followed by development
of a resting tremor, gait disturbances and visual learning deficits
at 8–9 weeks of age (Carter et al., 1999; Murphy et al., 2000).
There is support that mHTT may have detrimental effects in the
skeletal muscles of R6/2 mice due to poly(Q) aggregate accumu-
lation (Sathasivam et al., 1999; Moffitt et al., 2009)andformation
of these inclusions in myoblasts and myotubes have been con-
firmed in vitro (Orth et al., 2003). Alternatively, the toxicity of
triplet repeat-containing RNA and/or patially mis-spliced hunt-
ingtin gene (Htt) could be considered as an additional mechanism
of HD pathology (Sathasivam et al., 2013).
Transcriptional deregulation is a typical feature of HD pathol-
ogy in the brain (Luthi-Carter et al., 2002). A similar transcrip-
tional profile in skeletal muscles (quadriceps) from R6/2 mice,
HdhQ150 homozygous knock-in mice and HD patients has been
identified and that was consistent with a transition from fast-
twitch to slow-twitch muscle fiber types (Luthi-Carter et al.,
2002). On the other hand, based on immunohistochemistry both
type I and II muscles were atrophic. Although atrophy occurred
in both type fibers, there was more type I fibers in the R6/2 skele-
tal muscles. Hence, there was a conversion of type II fibers to
type I during the process of muscle atrophy (Ribchester et al.,
2004). However, these findings in pre-clinical settings are incon-
sistent with an increased glycolysis observed in human patients
(Ciammola et al., 2011). Metabolic adaptations similar to those
induced by diabetes or fasting are also present in HD mouse
models but neither metabolic disorder could explain the full phe-
notype of HD muscle (Strand et al., 2005). Consequently, at
the ultrastructural level, the sciatic nerve displayed abnormali-
ties in large myelinated fibers in the presymptomatic R6/2 mice.
A significant decrease in the axoplasm diameter of myelinated
neurons and increased number of degenerating myelinated fibers
were observed; although myelin thickness and unmyelinated fiber
diameter were not affected (Wade et al., 2008). The synaptic
transmission at the neuromuscular junction has also been stud-
ied in the R6/1 mouse model of HD. The morphological data
suggest that the innervation pattern of the neuromuscular junc-
tions in R6/1 muscles were normal in early symptomatic animals.
However, the size and frequency of miniature endplate potentials
were not changed in the R6/1 mice, while the amplitude of evoked
endplate potentials increased. Consistent with a pre-synaptic
increase of release probability, synaptic depression under high-
frequency was higher in R6/1 mice. No changes were detected in
size and dynamics of the recycling synaptic vesicle pool (Rozas
et al., 2011). In contrast, it has been shown that skeletal muscles of
R6/2 mice developed age-dependent denervation-like abnormal-
ities, including reduced endplate area, supersensitivity to acetyl-
choline, decreased sensitivity to mu-conotoxin and anode-break
action potentials (Ribchester et al., 2004). Moreover, the minia-
ture endplate potential (mEPP) amplitude was notably increased
while mEPP frequency was significantly reduced in R6/2 mice.
Severely affected R6/2 mice developed a progressive increase
in a number of motor endplates that fail to respond to nerve
stimulation but there was no constitutive sprouting of motor
neurons, even in severely atrophic muscles. In fact there was
no age-dependent loss of regenerative capacity of motor neu-
rons in R6/2 mice (Ribchester et al., 2004). Another group has
studied the membrane properties of skeletal muscles that con-
trol contraction in the same HD mouse model. Adult skeletal
muscle from R6/2 mice showed that the action potentials in dis-
eased muscles were more easily triggered and prolonged than in
wild type littermates. Furthermore, the expression of the muscle
chloride channel (ClC-1) and Kcnj2 (Kir2.1 potassium chan-
nel) transcripts were significantly reduced and defects in mRNA
processing were detected (Waters et al., 2013).
To better understand a mechanism underlying muscle wast-
ing in the R6/2 mouse model, key pathways governing protein
metabolism, apoptosis and autophagy were examined. R6/2 mice
exhibited increased adiposity and elevated energy expenditure
without altered food intake. A total protein synthesis was unex-
pectedly increased in the gastrocnemius muscle by 19%, which
was associated with over-activation of rapamycin mTOR signal-
ing (She et al., 2011). The transcript levels of androgens, like
muscle ring finger-1 and atrophy F-box, were markedly attenu-
ated during fasting and re-feeding. Additionally, the mRNA level
of several caspase genes involved in both extrinsic and intrinsic
apoptotic pathways, like CASPASE-3/7, −8, and −9, were ele-
vated (She et al., 2011). Indeed, the CASPASE-6 up-regulation
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Zielonka et al. Atrophy of skeletal muscles in HD
might be due to enhanced activity of the p53 in the mus-
cles obtained from HD patients and from two different HD
mouse models. It has been also shown that CASPASE-6 may
target (cleave) laminin A (Ehrnhoefer et al., 2014). It was sug-
gested that this phenomenon might be mitigated by a small
molecule pifithrin-alpha, an inhibitor of p53 transcriptional
activity (Ehrnhoefer et al., 2014).
Since mitochondrial dysfunction might play a crucial role in
HD pathology (Quintanilla and Johnson, 2009),theroleofPPAR
γcoactivator 1α(PGC-1α) has been carefully assessed (Lin et al.,
2005). Reduced levels of PGC-1αand its target genes in skele-
tal muscles of HD transgenic mice and HD subjects have been
found. Treatment with guanidinopropionic acid (GPA) led to an
increased expression level of AMPK, PGC-1αtarget genes and
the genes characteristic for oxidative phosphorylation, electron
transport chain and mitochondrial biogenesis. Oxygen consump-
tion in response to GPA treatment was significantly reduced in
myoblasts from HD patients (Chaturvedi et al., 2009). On the
other hand, knockdown of mutant HTT resulted in increased
PGC-1αexpression in HD myoblast, while PGC-1αrescue led to
increased expression of markers for oxidative muscle fibers and
reversalofbluntedresponseforGPAinHDmice(Chaturvedi
et al., 2009). These findings showed that impaired function of
PGC-1αplays a critical role in the skeletal muscles dysfunction
in HD. Also, possible pharmacologic intervention with a small
molecule could enhance PGC-1αfunction may exert therapeu-
tic benefits (Chaturvedi et al., 2009). In addition, atrophic fibers
of R6/2 mice showed increased fuchsinophilic aggregates and
reduced cytochrome coxidase by 15%. Complex I–dependent
respiration of HD mitochondria showed more sensitivity to inhi-
bition by Ca2+than in wild-type mitochondria (Gizatullina et al.,
2006). A summary of morphological and molecular characteris-
tics of skeletal muscles in pre-clinical and clinical settings has been
presented in Table 1 .
CAN WE DELAY HD PROGRESSION BY MODULATING
MUSCLE FUNCTION?
As it has been mentioned in the previous paragraph, enhancing
PGC-1αactivity might be a good strategy to improve skeletal
muscles function in HD. Indeed, pharmacologic treatment with
the pan-PPAR agonist bezafibrate restored the PGC-1α,PPARs
Table 1 | Summary of defects observed in muscle in the pre-clinical
and clinical HD settings.
Human Mouse models
Reduced muscle strength √√
Muscle atrophy Unknown √
Mitochondrial dysfunction √√
Inclusions formation √√
Transcriptional deregulation √√
Fast to slow twitch unknown √
Increased of adiposity and protein synthesis unknown √
Neuro-muscular junctions abnormalities unknown √
Increased caspase activity √√
and downstream genes to wild type levels. It also prevented con-
versionoftypeIoxidativetotypeIIglycolyticmusclefibersas
well as increased muscle mitochondria numbers. Finally, bezafi-
brate rescued lipid accumulation and apparent vacuolization of
brown adipose tissue in the HD mice (Johri et al., 2012).
The other strategy to improve muscle function in HD is
based on the heat shock machinery modulation that could sup-
press mHTT aggregation (Labbadia and Morimoto, 2013). The
R6/2 mice expressing an active heat shock transcription factor
1 (HSF1) isoform had reduced polyglutamine inclusion forma-
tion and improved body weight. Unexpectedly, the lifespan of
R6/2:HSF1Tg mice were significantly improved despite the fact
that active HSF1 was not expressed in the brain. These results
indicated that active HSF1 has a strong inhibitory effect on polyg-
lutamine aggregates formation in vivo (Fujimoto et al., 2005).
Recent studies also showed that HDAC4 function in the
cytoplasm (Mielcarek et al., 2013a) and its reduction, delayed
cytoplasmic aggregate formation and rescued neuronal and
cortico-striatal synaptic function in HD mouse models. This was
accompanied by an improvement in motor co-ordination, neu-
rological phenotypes and increased lifespan (Mielcarek et al.,
2013b). Given that HDAC4 has well-established functions in
skeletal muscle, muscle atrophy is a major symptom of HD and
that HDAC4 has been linked to disease progression in an ALS
mouse model, it is likely that genetic reduction of HDAC4 in
skeletal muscle was a contributing factor to the improved HD
phenotypes (Bruneteau et al., 2013).
SUMMARY
HD is a complex disease that has a peripheral component to
its pathophysiology. Transcriptional changes in the HD skele-
tal muscles were comparable to those observed in the different
brain regions and skeletal muscle wasting/atrophy is likely to be
an important portion of HD pathogenesis. Some of the molec-
ular and physiological changes in HD muscles can be detected,
even in the pre-symptomatic HD individuals. On the molecu-
lar level, mitochondrial dysfunctions, PPAR alpha signaling and
HSF1 activation were identified as major players in the muscle
HD-related pathology. The major pathological pathways iden-
tifiedinskeletalmuscleshavebeensummarizedinFigure 1.
However, many aspects of HD neuromuscular transmission and
FIGURE 1 | Summary of pathological events identified in the skeletal
muscles in HD.
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Zielonka et al. Atrophy of skeletal muscles in HD
muscle physiology remain unanswered and need to be studied
more extensively. The proof of concept studies clearly showed that
by improving muscle function in HD mouse models, the progres-
sion of disease onset could be delayed and the lifespan extended.
Therefore this makes skeletal muscles an attractive target for
future therapies. Two key signaling pathways, i.e., Insulin like
growth Factor IGF and GDF-8/myostatin, have emerged in recent
years to be potent regulators of skeletal muscle size. Moreover,
several studies emphasized a role of hyperacetylation in muscle
wasting. Therefore there is a need for more pre-clinical and clini-
cal studies that will unravel the mechanism of HD skeletal muscles
pathology, leading to potential therapies in HD. Further work is
necessary in order to fully appreciate the complexity of the path-
ways that are affected during HD progression. Indeed, emerging
evidence has clearly indicated that peripheral tissues are as much
affected by the expression of the mutant huntingtin as the Central
Nervous System. Furthermore, the possibility to test the effect
of new drugs directly on human peripheral tissues is a new and
exciting research area.
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Conflict of Interest Statement: Conflict of Interest Statement: The authors declare
that the research was conducted in the absence of any commercial or financial
relationships that could be construed as a potential conflict of interest.
Received: 31 July 2014; accepted: 13 September 2014; published online: 06 October
2014.
Citation: Zielonka D, Piotrowska I, Marcinkowski JT and Mielcarek M (2014) Skeletal
muscle pathology in Huntington’s disease. Front. Physiol. 5:380. doi: 10.3389/fphys.
2014.00380
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