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First published online May 26, 2006
Journal of Experimental Biology 209, 2265-2275 (2006)
Published by The Company of Biologists 2006
doi: 10.1242/jeb.02182
Review Article: Phenotypic Plasticity in Skeletal Muscle |
Coordination of metabolic plasticity in skeletal muscle
1 School of Kinesiology and Health Science, York University, Toronto,
Ontario, M3J 1P3, Canada
2 Department of Biology, York University, Toronto, Ontario, M3J 1P3,
Canada
* Author for correspondence (e-mail: dhood{at}yorku.ca)
Accepted 21 February 2006
Summary
Skeletal muscle is a highly malleable tissue, capable of pronounced
metabolic and morphological adaptations in response to contractile activity
(i.e. exercise). Each bout of contractile activity results in a coordinated
alteration in the expression of a variety of nuclear DNA and mitochondrial DNA
(mtDNA) gene products, leading to phenotypic adaptations. This results in an
increase in muscle mitochondrial volume and changes in organelle composition,
referred to as mitochondrial biogenesis. The functional consequence of this
biogenesis is an improved resistance to fatigue. Signals initiated by the
exercise bout involve changes in intracellular Ca2+ as well as
alterations in energy status (i.e. ATP/ADP ratio) and the consequent
activation of downstream kinases such as AMP kinase and
Ca2+-calmodulin-activated kinases. These kinases activate
transcription factors that bind DNA to affect the transcription of genes, the
most evident manifestation of which occurs during the post-exercise recovery
period when energy metabolism is directed toward anabolism, rather than
contractile activity. An important protein that is affected by exercise is the
transcriptional coactivator PGC-1
, which cooperates with multiple
transcription factors to induce the expression of nuclear genes encoding
mitochondrial proteins. Once translated in the cytosol, these mitochondrially
destined proteins are imported into the mitochondrial outer membrane, inner
membrane or matrix space via specific import machinery transport
components. Contractile activity affects the expression of the import
machinery, as well as the kinetics of import, thus facilitating the entry of
newly synthesized proteins into the expanding organelle. An important set of
proteins that are imported are the mtDNA transcription factors, which
influence the expression and replication of mtDNA. While mtDNA contributes
only 13 proteins to the synthesis of the organelle, these proteins are vital
for the proper assembly of multi-subunit complexes of the respiratory chain,
when combined with nuclear-encoded protein subunits. The expansion of skeletal
muscle mitochondria during organelle biogenesis involves the assembly of an
interconnected network system (i.e. a mitochondrial reticulum). This expansion
of membrane size is influenced by the balance between mitochondrial fusion and
fission. Thus, mitochondrial biogenesis is an adaptive process that requires
the coordination of multiple cellular events, including the transcription of
two genomes, the synthesis of lipids and proteins and the stoichiometric
assembly of multisubunit protein complexes into a functional respiratory
chain. Impairments at any step can lead to defective electron transport, a
subsequent failure of ATP production and an inability to maintain energy
homeostasis.
Key words: mitochondrial biogenesis, transcription factors, reactive oxygen species, calcium signaling, mitochondrial protein import
Introduction
Skeletal muscle exhibits remarkable adaptive capabilities in response to a
number of physiological and pathophysiological conditions. In particular, one
of the most dramatic phenotypic alterations occurs in mitochondria in response
to exercise or chronic contractile activity. This is most evident in
low-oxidative, white muscle, which has an initial mitochondrial content
ranging from only 1 to 3% of the total cellular volume
(Hoppeler, 1986
). Contractile
activity-induced mitochondrial adaptations in muscle are highly specific and
are dependent upon the type of exercise (i.e. resistance vs
endurance) as well as its frequency, intensity and duration. In addition, the
recovery period following the exercise bout is a time of rapid, transient
changes in gene expression, which contributes to the initial stages of the
adaptation of each period of contractile activity. The physiological benefits
of mitochondrial adaptations in muscle are an alteration in metabolic
preference, with a greater reliance on lipid, rather than carbohydrate,
metabolism. This reduces the formation of lactic acid, attenuates the loss of
glycogen, reduces high-energy phosphate utilization and reduces muscle
fatigue. Mitochondrial adaptations in response to exercise are generally
referred to as `mitochondrial biogenesis'. In the context of this review,
mitochondrial biogenesis will be used synonymously with the broader term
`metabolic plasticity', since mitochondrial adaptations to exercise represent
the dominant adaptive response, while glycolytic adaptations are minimal.
Mitochondrial biogenesis within muscle consists of two possible mutually
inclusive alterations: (1) an increase in mitochondrial content per gram of
tissue and/or (2) a change in mitochondrial composition, with an alteration in
mitochondrial protein-to-lipid ratio. Although this phenomenon resulting from
exercise has long been established
(Holloszy, 1967), many of the
detailed molecular mechanisms remain to be identified. This is important for
our understanding of the general mechanisms of organelle assembly, as well as
the pathophysiology of mitochondrially based diseases. Thus, mitochondrial
biogenesis induced by chronic exercise is now recognized to have implications
for a broader range of health issues than just the enhancement of endurance
performance. Changes in mitochondrial plasticity produced by exercise are a
result of multiple molecular events (Hood,
2001) (Fig. 1).
These include signaling events to initiate biogenesis, the transcription of
nuclear genes, the import of nuclear gene products into the organelle, the
replication and transcription of mtDNA, mRNA translation into protein and the
correct assembly of proteins into a functional stoichiometry. The present
review will focus on (1) the initiation of metabolic plasticity, beginning
with the signals leading to gene expression at the onset of exercise training,
(2) the important transcriptional regulatory proteins PGC-1 (peroxisome
proliferators-activated receptor-
coactivator-1) and
mitochondrial transcription factor A (Tfam) and (3) current progress in
understanding mitochondrial assembly in muscle.
|
Calcium, ATP turnover and reactive oxygen species
At the onset of contractile activity, a number of rapid events occur that
form part of the initial signaling process leading to downstream protein and
lipid synthesis. These changes include Ca2+ flux, ATP turnover and
the stimulation of oxygen consumption within the contracting muscle cells.
Accumulating evidence supports the link between alterations in intracellular
Ca2+ dynamics and distinctive programs of gene expression that
establish phenotypic diversity among skeletal myofibers
(Chin et al., 1998;
Freyssenet et al., 1999;
Freyssenet et al., 2004;
Ojuka et al., 2003;
Olson and Williams, 2000;
Wu et al., 2000).
Ca2+ has been implicated as an important signal in the upregulation
of several nuclear genes encoding mitochondrial proteins
(Ojuka et al., 2003), in part
via a protein kinase C (PKC)-mediated pathway
(Freyssenet et al., 1999).
However, although the expression of a number of genes encoding mitochondrial
proteins is increased in response to elevations in intracellular
Ca2+, some are not, or follow a different time course of induction
(Freyssenet et al., 2004).
Thus, it is probable that elevations in Ca2+ only partially mediate
the contractile activity-induced changes in mitochondrial biogenesis, and that
it forms part of a more complex signaling pathway, perhaps involving
AMP-activated protein kinase (AMPK) (Fig.
1) (Bergeron et al.,
2001; Irrcher et al.,
2003; Putman et al.,
2003; Winder et al.,
2000; Zong et al.,
2002).
The AMPK cascade is activated by cellular stresses that reduce the ATP/ADP
ratio and elevate AMP as a result of myokinase activity. This can occur either
by inhibiting ATP production or by accelerating ATP consumption. AMPK activity
is increased in skeletal muscle with exercise
(Fujii et al., 2000), as a
result of 5-aminoimidazole-4-carboxamide riboside (AICAR) treatment and during
chronic administration of the creatine analogue ß-GPA
(Bergeron et al., 2001).
ß-GPA treatment is associated with increased cytochrome c
content, mitochondrial density and DNA binding activity of nuclear respiratory
factor-1 (NRF-1). Thus, treatment with this agent appears to recapitulate the
adaptive responses induced by endurance training or chronic contractile
activity. The effect of ß-GPA is mediated by AMPK, since enzyme
inactivation ablates the ß-GPA-induced mitochondrial biogenesis
(Zong et al., 2002). Direct
activation of AMPK using AICAR also mimics many of the metabolic changes
evident as a result of chronic exercise training, such as augmented levels of
citrate synthase activity, 
-aminolevulinic acid synthase and uncoupling
protein-3 content (Putman et al.,
2003; Winder et al.,
2000). Therefore, by sensing the energy status of the muscle cell,
AMPK appears to be an important regulator of mitochondrial content.
However, the necessity for a multiplicity of pathways involved in metabolic
plasticity is underscored by a recent study that showed that the
exercise-induced activation of a number of metabolic genes was not impaired in
either AMPK1 or AMPK2 knockout animals
(Jorgensen et al., 2005).
Thus, under those conditions, other signaling events, possibly involving
Ca2+ or the remaining AMPK isoform, may compensate for the
reduced total AMPK activity to regulate metabolic gene activation in skeletal
muscle. In addition, it is likely that signals involving Ca2+ and
energy deficits act in concert to promote metabolic plasticity. Evidence for
this is found in cells with reduced or mutated mitochondrial DNA (mtDNA), in
which ATP levels are reduced, intracellular Ca2+ levels are
elevated (Moudy et al., 1995)
and nuclear gene expression is activated
(Biswas et al., 1999;
Joseph et al., 2004). These
data suggest the existence of a retrograde intracellular communication network
between the mitochondrial and nuclear genomes. In these cells, the reduced ATP
levels promote the elevation of intracellular calcium levels, resulting in the
activation of calcium-responsive genes, including calcineurin and
cAMP-responsive elements binding proteins (CREB)
(Arnould et al., 2002;
Biswas et al., 1999). The
expression of several transcription factors such as NRF-1 and Tfam
(Miranda et al., 1999), as
well several key cytochrome c oxidase (COX) subunits
(Biswas et al., 1999;
Marusich et al., 1997), is
altered. The redundancy and complementarity in signal transduction illustrated
by this energy depletion condition is an important example of the cellular
compensatory mechanisms used to ensure adequate organelle synthesis for cell
survival.
As part of the process of ATP production, molecular oxygen undergoes a
four-electron reduction catalyzed by COX. This process accounts for
95–98% of the total oxygen consumption. The small remaining oxygen
fraction can undergo a one-electron reduction with the production of reactive
oxygen species (ROS) (Fig. 1).
ROS production is lower in maximally activated state 3 respiration than in
low-level, resting state 4 respiration, indicating that ROS production is
inversely related to the rate of oxygen consumption. This is evident in
mitochondria isolated from both the subsarcolemmal and intermyofibrillar
regions of the myocyte (Adhihetty et al.,
2005). The higher ROS production in the subsarcolemmal
mitochondrial subfraction may contribute to the greater potential of this
mitochondrial subfraction to adapt under conditions of exercise
(Hood, 2001) or disease
(Ritov et al., 2005). However,
it is now recognized that ROS production in muscle arises not only from
mitochondria but also from other intracellular and extracellular reactions
(Pattwell and Jackson, 2004).
Since ROS production increases in muscle during contractile activity
(Pattwell et al., 2004) and
with acute exercise (Davies et al.,
1982), and mitochondrial sources of ROS are reduced during active
respiration, these alternative sources of ROS must increase in importance
during contractile activity.
Recent studies have indicated that the chemically induced production of ROS
can lead to mitochondrial reticulum elongation and branching complexity in
fibroblast cells (Koopman et al.,
2005a). In addition, patients with mitochondrial complex I
deficiency have elevated rates of ROS production and demonstrate similar
adaptive changes in mitochondrial morphology
(Koopman et al., 2005b). Thus,
it has become clear that ROS are important signals involved in mitochondrial
adaptations and possibly in the mitochondrial responses to exercise. ROS can
act through several different pathways of signal transduction, making use of
signaling cascades such as protein kinases, phosphatases, phospholipases and
Ca2+. Downstream transcription factors that are affected by
intracellular ROS include NF-
B, AP-1, HSF, Egr-1 and p53
(Pattwell and Jackson, 2004),
resulting in their altered transcriptional activity. For example, it has
recently been reported that IB kinase and NF-B are activated in
skeletal muscle by exercise. While this pathway represents a likely
ROS-activated regulator of gene expression during, and following, contractile
activity (Ho et al., 2005),
the precise contribution of each of these signaling cascades and their
downstream targets during exercise remains an exciting avenue of investigation
in metabolic plasticity.
Protein kinase activation by exercise
The alterations in cellular homeostasis brought about by contractile
activity, as noted above, affect the activation of kinases and phosphatases
resulting in the posttranslational modification of proteins
(Nader and Esser, 2001;
Sakamoto et al., 2002). In the
context of exercise, this rapid response is related to the type, intensity and
duration of the contractile activity, as well as to the muscle fiber type
(Bodine et al., 2001;
Nader and Esser, 2001;
Sakamoto et al., 2002).
Multiple kinases, including AMPK, Akt and the mitogen-activated protein
kinases (MAPKs) ERK1/2 and p38, are involved in the regulation of DNA
transcription through the phosphorylation of nuclear transcription factors.
This either enhances or inhibits the ability of transcription factors to bind
DNA, affecting target gene transcription
(Bergeron et al., 2001;
Sakamoto et al., 2002;
Sandri et al., 2004). Chronic
activation of these signaling cascades brought about by muscle contractions
during intermittent bouts of acute physical activity can result in either (1)
nuclear and mitochondrial gene expression, leading to phenotype adaptations
such as mitochondrial biogenesis (Hood,
2001) and improved endurance performance, or (2) myofiber
hypertrophy and augmented force development
(Glass, 2005). For example,
the activation of the p38 MAPK pathway participates in contractile
activity-induced PGC-1 gene expression in skeletal muscle through the
phosphorylation of proteins that include ATF2
(Akimoto et al., 2005). In
addition, low-frequency pacing of skeletal muscle reflective of endurance
activity also induced an AMPK–PGC-1 signaling pathway
(Atherton et al., 2005). As
described below, this induction of PGC-1 is an important initial
mechanism involved in mitochondrial adaptations to contractile activity. In
addition, a considerable amount of recent progress has been made in
understanding the signaling pathways that mediate skeletal muscle hypertrophy,
primarily via the activation of Akt-mediated events
(Kubica et al., 2005;
Lai et al., 2004), as well as
muscle atrophy, largely via signaling pathways involving FOXO,
Atrogin-1 and MURF-1 (Glass,
2005; Sandri et al.,
2004). Given the multiplicity of signaling pathways that are
active in muscle, classifying the specific cascades involved in these
divergent forms of muscle plasticity is a task that requires continued
investigation.
Gene expression response to contractile activity and recovery
The early cellular signals that are associated with contractile activity
are known to induce the subsequent expression of mRNAs encoding transcription
factors that regulate changes in skeletal muscle phenotype
(Irrcher and Hood, 2004;
Puntschart et al., 1998).
Several studies have demonstrated that changes in the mRNA expression of
transcription factors precede the contractile activity-induced regulation of
mitochondrial and metabolic plasticity in skeletal muscle
(Connor et al., 2001;
Irrcher et al., 2003;
Michel et al., 1994;
Pilegaard et al., 2003;
Xia et al., 1997). These
include the induction of a family of immediate early genes (c-fos,
c-jun), the early growth response gene-1 (Egr-1), specificity
protein 1 (Sp1) and nuclear respiratory factor-1 (NRF-1), which respond to
both acute and chronic contractile activity
(Abu-Shakra et al., 1993;
Connor et al., 2001;
Irrcher and Hood, 2004;
Michel et al., 1994;
Murakami et al., 1998;
Neufer et al., 1998;
Puntschart et al., 1998;
Takahashi et al., 1993). Egr-1
and Sp1 are known to be involved in regulating the transcription of cytochrome
c, a nuclear-encoded protein of the electron transport chain
(Connor et al., 2001;
Freyssenet et al., 2004),
while NRF-1 is involved in the transcriptional activation of an even greater
diversity of nuclear genes encoding mitochondrial proteins
(Kelly and Scarpulla, 2004),
including the newly discovered mtDNA transcription factors TFB1M and TFB2M
(Gleyzer et al., 2005). Acute
contractile activity also results in a transient increase in transcriptional
co-activator PGC-1 promoter activity along with an increase in
PGC-1 mRNA (Akimoto et al.,
2004) and protein (Baar et al.,
2002). These increases appear to be dependent on the MEF2 and cAMP
response element (CRE) binding sites within the PGC-1 promoter, since
mutation of these elements abolished contractile activity-induced
transcriptional activation of the PGC-1 promoter
(Akimoto et al., 2004).
Metabolic plasticity and adaptations to contractile activity are augmented
by an intervening recovery period between bouts of activity
(Michel et al., 1994;
Neufer et al., 1998;
Pilegaard et al., 2003;
Puntschart et al., 1998;
Takahashi et al., 1993). This
applies to transcription factor expression
(Irrcher and Hood, 2004), as
well as the expression of several genes that encode various regulatory and
metabolic proteins, including PGC-1. The activation of most of these
genes takes place during the initial 1–4 h of recovery, returning to
basal levels within 24 h (Pilegaard et
al., 2000). This activation appears to be markedly attenuated if
glycogen repletion post-exercise is maximized by the consumption of a high
carbohydrate diet. By contrast, the response is increased if glycogen
repletion is inhibited by the consumption of a low carbohydrate diet
(Pilegaard et al., 2005).
Thus, the enhanced gene expression response post-exercise is likely related to
ATP availability, involving a shift in ATP utilization away from contractile
activity toward the energy requirements of transcription, translation and
post-translational modification reactions, as well as the availability of
carbohydrate and lipid sources of energy.
Mitochondrial transcription factor A (Tfam)
Mitochondria contain multiple circular 16 kb genomes (mtDNA)
(Fig. 1) that encode 13
protein, 22 tRNA and 2 rRNA genes, representing only a small fraction of the
total number of proteins involved in the production and synthesis of
mitochondria. The remaining mitochondrial proteins are encoded by the nuclear
genome and must be imported into the organelle via the protein import
machinery (Fig. 1). Thus,
mitochondrial biogenesis requires the co-expression of both the nuclear and
mitochondrial genomes to ensure the proper assembly and expansion of the
mitochondrial reticulum. mtDNA replication and transcription are regulated
independently of the nuclear genome but are dependent on the expression and
import of a number of nuclear-derived transcription and regulatory factors.
One of the most important proteins involved in these processes is Tfam. Tfam
is imported into mitochondria via Tom20
(Grey et al., 2000) and it has
a presequence that is cleaved during the import process. Within mitochondria,
Tfam is responsible for binding to the regulatory D-loop region of mtDNA and
is involved in mtDNA transcription and replication
(Larsson et al., 1998). Recent
work has indicated that Tfam is enriched in a nucleoid complex with mtDNA
within the organelle (Legros et al.,
2004), possibly serving to protect mtDNA from excessive
ROS-induced damage or helping maintain mtDNA stability. Indeed, Tfam levels
are closely associated with mtDNA levels in patients with mtDNA depletion
(Larsson et al., 1994). The
reduced levels of Tfam under these conditions may be a result of impaired
translation or import into the organelle
(Larsson et al., 1994). Tfam
is essential for embryonic development, and heterozygous knockout animals have
reduced mtDNA copy number, transcription and respiratory chain dysfunction
(Larsson et al., 1998;
Li et al., 2000).
Interestingly, Tfam levels have been reported to increase in human muscle
(Lezza et al., 2001) and rat
tissues (Dinardo et al., 2003)
during aging, in a possible effort to maintain mtDNA stability. Exercise
training also stimulates the expression of Tfam in humans
(Bengtsson et al., 2001), as
does chronic contractile activity produced by electrical stimulation of
skeletal muscle in rats (Gordon et al.,
2001). The increase in Tfam protein expression is preceded by a
time-dependent increase in Tfam mRNA expression, import into the organelle and
mtDNA binding (Gordon et al.,
2001). Although a complete picture of the transcriptional
regulation of the Tfam gene is lacking, it appears that NRF-1 is important in
conferring transcriptional activation
(Choi et al., 2004). The
increase in the level of this transcription factor as an early event at the
onset of contractile activity (Irrcher et
al., 2003; Murakami et al.,
1998) is likely important in mediating the subsequent involvement
of Tfam in exercise-induced mitochondrial biogenesis. Recent work indicates
that NRF-1 is also involved in the transcriptional regulation of accessory
mtDNA transcription factors TFB1M and TFB2M
(Gleyzer et al., 2005). The
expression and function of these during exercise-induced metabolic plasticity
remains to be determined.
Peroxisome proliferator-activated receptor- coactivator-1 (PGC-1)
The discovery of PGC-1 represents a major advancement in the
elucidation of the molecular mechanisms driving mitochondrial biogenesis.
PGC-1 was initially cloned from a brown fat cell library and was found
to play a key role in linking the actions of nuclear hormone receptors to the
transcriptional control of adaptive thermogenesis in brown fat, of which the
biogenesis of mitochondria is a key process
(Puigserver et al., 1998).
Given the role of skeletal muscle in adaptive thermogenesis, PGC-1 was
found to be equally important in controlling mitochondrial content in this
tissue (Wu et al., 1999). In
fact, both gain- and loss-of-function studies in cell culture and in
vivo point to PGC-1 as an important regulator of energy metabolism
and mitochondrial biogenesis in tissues relying mainly on oxidative metabolism
for ATP production (i.e. brain, heart, skeletal muscle, brown fat and liver)
(Leone et al., 2005;
Lin et al., 2004;
Puigserver et al., 1998;
Wu et al., 1999).
In heart and skeletal muscle, the ectopic expression of PGC-1
induces mitochondrial biogenesis and increases cellular respiration
(Lehman et al., 2000;
St-Pierre et al., 2003;
Wu et al., 1999). The
molecular mechanisms involved, at least in skeletal muscle, include the
upregulation of Tfam transcription via co-activation of NRF-1 and
NRF-2 (Wu et al., 1999).
Thus, by this mechanism, PGC-1 is able to coordinate nuclear and
mitochondrial gene expression, a key requirement in the control of organelle
biogenesis.
Mechanism of PGC-1 action and regulation of gene expression
PGC-1 is part of an important family of transcriptional
co-activators that includes PGC-1ß and PGC-related co-activator [PRC; see
Lin et al. (Lin et al., 2005),
for review]. These interact with a broad spectrum of nuclear hormone receptors
and transcription factors to activate physiological processes intrinsically
linked with energy metabolism in tissues possessing a high mitochondrial
content. Both PGC-1ß and PRC share a high degree of homology with
PGC-1, in particular within domains necessary for protein–protein
interactions. They also share some redundancy with respect to the manner in
which they function, although the extent of this has yet to be defined in the
context of the coordination of metabolic plasticity in skeletal muscle.
The basis for the PGC-1-mediated regulation of mitochondrial gene
expression and biogenesis lies in its ability to transcriptionally activate a
variety of transcription factors, as noted above, and also in its association
with a growing list of proteins that are involved in regulating PGC-1
activity. These include proteins that alter PGC-1 transcriptional
activity via post-translational modifications or
protein–protein interactions. For example, PGC-1 activity in
skeletal muscle is positively regulated by the activation of the p38 MAPK
pathway. Knutti et al. first described that the biological activity of
PGC-1 was tightly coupled to the binding of a putative repressor
protein (Knutti et al., 2001).
Upon phosphorylation by p38 MAPK, the inhibitory effect of the repressor
protein was relieved, permitting PGC-1 to recruit, interact with and
co-activate proteins to induce target gene expression
(Fan et al., 2004;
Knutti et al., 2001).
Puigserver et al. subsequently described the p38 MAPK-mediated phosphorylation
of PGC-1 on ser/thr residues within its inhibitory domain
(Puigserver et al., 2001).
This action was shown to stabilize and increase the transcriptional potency of
PGC-1 protein and to stimulate mitochondrial respiration. The
subsequent identification of the repressor protein first characterized by
Knutti et al. as p160MBP
(Knutti et al., 2001)
permitted the elucidation of distinct dual actions of p38 MAPK in stimulating
mitochondrial biogenesis via PGC-1: (1) the direct effect on
increasing PGC-1 stability via ser/thr phosphorylation and (2)
the augmentation of PGC-1 transcriptional activity via the
disruption of the PGC-1/p160MBP interaction. It appears that
p160MBP is functional in skeletal muscle, since overexpression of
this protein in PGC-1 expressing C2C12 muscle
cells suppressed mitochondrial oxygen consumption and gene expression
(Fan et al., 2004). Thus, the
phosphorylation and activation of p38 MAPK are likely vital events at the
onset of contractile activity-induced mitochondrial biogenesis.
It is also becoming clear that, in addition to post-translational
phosphorylation, the acetylation status of PGC-1 represents an
important mechanism that could regulate its transcriptional activity, and thus
affect mitochondrial biogenesis. For example, PGC-1 has been shown to
associate with histone acetyltransferases such as CBP/p300 and SRC-1 to
activate the transcription of target genes
(Puigserver et al., 1998) and
with the NAD-dependent deacetylase SIRT1. In liver, the SIRT1-mediated
deacetylation of PGC-1 stimulates the up-regulation of gluconeogenic
genes and liver glucose output without affecting mitochondrial gene expression
(Rodgers et al., 2005) whereas
in neural cells, deacetylation of PGC-1 causes a reduction in cellular
oxygen consumption (Nemoto et al.,
2005). Interestingly, these results suggest that the cellular
context plays an important role in determining the ultimate effect of
SIRT1-mediated PGC-1 deacetylation. It is currently unknown whether
PGC-1 and SIRT1 physically interact to modulate mitochondrial function
in skeletal muscle.
Despite indications that PGC-1 is a key player in mitochondrial
biogenesis, two recent independent studies using loss-of-function strategies
to investigate the necessity of PGC-1 in inducing mitochondrial
biogenesis have determined that PGC-1 is not an absolute requirement
for the induction of mitochondrial biogenesis
(Arany et al., 2005;
Leone et al., 2005). However,
these studies used different loss-of-function strategies to eliminate
PGC-1 expression, resulting in discrepant phenotypes and metabolic
profiles. Thus, precise conclusions on the necessity of PGC-1 for
mitochondrial biogenesis, and the possible compensatory roles of other
transcriptional co-activators, require further study, particularly in the
context of exercise.
Regulation of PGC-1 gene expression
Since PGC-1 is an important regulator of mitochondrial biogenesis,
it follows that the transcription of PGC-1 plays an important
regulatory role in the induction and maintenance of mitochondrial content in
skeletal muscle. Recently, several signaling pathways directly influencing the
activity of the PGC-1 promoter have been identified. The best
characterized are the signaling events occurring through a proximal cAMP
responsive element (CRE) via CREB, a CRE-binding protein. Activation
of CREB via phosphorylation appears to be an important step in a
cascade of events that results in the integration of several signaling
pathways leading to the execution of PGC-1-mediated actions in various
tissues, including adaptive thermogenesis in brown fat
(Cao et al., 2004;
Puigserver et al., 1998),
induction of gluconeogenic genes in the liver
(Herzig et al., 2001) and
calcium signaling through calcium/calmodulin-dependent protein kinase (CaMK)
and calcineurin (CnA) in skeletal muscle and heart
(Handschin et al., 2003;
Schaeffer et al., 2004). Other
signaling mechanisms involved in regulating the transcriptional activity of
PGC-1 have been described, including the p38 MAPK-mediated activation
of ATF2, which leads to enhanced ATF2–CRE binding and activation of the
PGC-1 promoter (Akimoto et al.,
2005). Interestingly, some transcription factors that PGC-1
co-activates also regulate PGC-1 promoter activity. An example of this
autoregulatory mechanism was recently described in the MEF2-mediated
regulation of PGC-1 in skeletal muscle. It was shown that MEF2 proteins
bind to the PGC-1 promoter causing transcriptional activation, which is
enhanced when PGC-1 is ectopically expressed
(Handschin et al., 2003). The
continued identification of factors that regulate PGC-1 transcription
will help us understand the stimulus-specific regulation of PGC-1
expression, eventually leading to the identification of potential therapeutic
strategies.
Response to exercise
It is known that single bouts of exercise can elicit changes in the
expression of a number of transcription factors implicated in mitochondrial
biogenesis, including PGC-1. When exercise is performed successively
over a period of time, progressive increases in the accumulation of
PGC-1 protein and the important co-activated transcription factor
NRF-1, as well as Tfam, the downstream target of PGC-1 and NRF-1, are
observed (Baar et al., 2002;
Gordon et al., 2001;
Irrcher et al., 2003;
Terada et al., 2002). Thus,
the exercise-induced coordination of these increases establishes the
likelihood that these proteins play important roles in mediating the
mitochondrial adaptations to exercise. The recent finding that skeletal muscle
function in PGC-1–/– mice is reduced, but not
completely compromised, supports this hypothesis
(Leone et al., 2005). However,
the absence of a complete compromise in muscle function in
PGC-1–/– animals highlights the potential of
discovering novel and unexplored mechanisms of exercise-induced adaptations in
muscle that are not mediated by PGC-1. Thus, a more complete
characterization of the existing PGC-1 family members and/or identification of
novel PGC-1-like co-activators will be important in further elucidating the
exercise-mediated induction and maintenance of mitochondrial content.
Mitochondrial multi-subunit complex assembly in health and disease
The ability of the mitochondrion to function as the predominant
energy-producing organelle within a cell is dependent on the electron
transport chain (ETC) complexes that are embedded within the inner
mitochondrial membrane. The assembly of these large hetero-oligomeric
complexes is unique because it requires the coordinated incorporation of
subunits from both the nuclear and mitochondrial genomes. In recent years,
defects in energy metabolism, which arise from mutations in mitochondrially
associated genes, have been shown to serve as the molecular basis for a
plethora of human diseases (Shoubridge,
2001; Wallace,
1992). These mitochondrial diseases, which usually manifest in
early childhood, primarily affect high energy-producing tissues such as the
brain, muscle and heart (Wallace,
1992).
The most widely studied ETC complex is COX, the terminal electron acceptor
in the ETC, which converts oxygen to water and provides the protons required
for ATP synthesis (Nijtmans et al.,
1998). The assembly of the 200 kDa mammalian COX holoenzyme is a
highly regulated process that involves the sequential incorporation of 13
subunits and several prosthetic groups into specific intermediate subcomplexes
(Nijtmans et al., 1998;
Wielburski and Nelson, 1983).
COX assembly is further complicated by the fact that COX subunits are of both
nuclear and mitochondrial origin and that assembly requires numerous
nuclear-encoded accessory proteins including SCO1, SCO2, COX 10 and Surf-1
(Barrientos et al., 2002;
Carr and Winge, 2003). Three
of the subunits that form the catalytic and structural core of the enzyme (COX
I–III) are transcribed and translated by mtDNA and are subsequently
incorporated into the inner membrane
(Capaldi, 1990). The remaining
smaller subunits are coded for in the nucleus and must therefore be targeted
and imported into the organelle. Currently, the exact function of these
nuclear-encoded subunits in holoenzyme assembly is not known, but the
transcriptional regulation of the genes encoding these subunits is being
elucidated (Lenka et al.,
1998). The existence of tissue-specific isoforms of these
nuclear-encoded enzymes suggests that they may function to alter the catalytic
activity of the COX complex during altered states of energy metabolism within
different tissues (Kadenbach et al.,
1990; Linder et al.,
1995). Furthermore, in rat liver cells, the dissociation of
numerous nuclear-derived subunits results in an increase in the enzymatic
activity of the COX holoenzyme (Kadenbach
et al., 1991). Based on these observations, it is generally
believed that these smaller proteins may play an important role in regulating
the stability and maintenance of the COX holoenzyme complex
(Kadenbach et al., 1991).
The mitochondrial assembly of multi-subunit complexes can be altered under
various physiological and pathological conditions
(Hood, 2001). In iron
deficiency, the lack of functional heme results in decreased mitochondrial
mass within the muscle, as well as mitochondria with abnormal structure
(Hood et al., 1992). In
addition, impaired COX function arising from mutations in mitochondrially
encoded COX enzymes or assembly factor genes has been reported to be the
primary cause of COX deficiency associated with ETC defects
(Nijtmans et al., 1998). Using
a blue-native polyacrylamide gel electrophoresis (BN-PAGE) approach
(Schagger and von Jagow,
1991), the assembly of specific subunits into nascent complexes
can be directly monitored, and alterations in the assembly profile that may be
the underlying molecular cause of several mitochondrially associated diseases
can be examined. A prime example of the importance of this assembly process
has recently been demonstrated with the finding that patients harboring
mutations in the Surf-1 COX assembly gene have an accumulation of unassembled
COX subunits and intermediate complexes, leading to reduced COX activity
(Tiranti et al., 1998;
Williams et al., 2004).
Furthermore, the use of BN-PAGE, in conjunction with denaturing (SDS)
electrophoretic separation in the second dimension, has allowed for the
characterization of the assembly pathway of other ETC complexes such as
Complex I and the ATP synthase complex. These studies have subsequently led to
the identification of assembly defects that impair the stability of the
holoenzyme complexes (Antonicka et al.,
2003; Nijtmans et al.,
2001). Thus, these electrophoretic techniques appear to be very
useful for the study of mitochondrial complex assembly in physiological and
pathological conditions.
Despite an emergence of studies examining mitochondrial complex assembly,
the molecular mechanisms regulating the biosynthesis of these complexes remain
generally unresolved, particularly in mammalian cells. The series of steps in
mitochondrial assembly that is best studied is that of protein import into the
matrix of the organelle (Hood and Joseph,
2004). Precursor proteins translated in the cytosol are directed
to the multi-subunit translocase of the outer membrane (Tom) complex by
molecular chaperones such as mitochondrial import stimulating factor (MSF) or
cytosolic heat-shock protein 70 (Hsp70). The N-terminal targeting sequence of
the precursor protein interacts with outer membrane receptors such as Tom20 or
Tom70, the protein is then subjected to ATP-dependent unfolding and is
subsequently drawn into the matrix of the mitochondrion through the
translocase of the inner membrane (TIM) complex. This occurs via the
ATP-dependent action of mtHsp70 and accessory proteins. Once inside the
matrix, the targeting sequence is cleaved, and the mature protein is refolded
into a functional component for Krebs cycle or for other matrix functions.
Divergent import pathways are utilized for import into the outer membrane,
intermembrane space or inner membrane
(Koehler, 2004;
Wiedemann et al., 2004).
Mitochondrial plasticity in muscle is dependent on the adaptive capacity of
the protein import pathway, since approximately 1000 proteins localized within
the organelle require entry via this route during biogenesis. In
muscle, protein import rates into subsarcolemmal (SS) mitochondria are less
than that for mitochondria isolated from the intermyofibrillar (IMF) region,
in part because of differential amounts of intramitochondrial ATP and
divergent rates of respiration. Chronic contractile activity of muscle results
in an enhanced rate of import of precursor proteins into the matrix of both
mitochondrial subfractions (Gordon et al.,
2001; Takahashi et al.,
1998). This is likely due to the greater expression of protein
import machinery components, such as Tom20 and mtHsp70. Tom20 appears to be
critical for the initial recognition and import of precursor proteins, since
antisense-induced reductions in Tom20 expression lead to parallel declines in
import rate (Grey et al.,
2000).
Thus, there is conclusive evidence that the import and assembly of multi-subunit complexes are modified during altered states of mitochondrial biogenesis. These findings demonstrate another level of control through which mitochondria maintain their protein composition, as well as cellular homeostasis, in response to physiologically induced increases in mitochondrial function.
Future directions in metabolic plasticity in muscle
This review has focused on the currently viewed vital proteins and
processes involved in regulating mitochondrial biogenesis in muscle. Much
remains to be learned in areas such as the assembly of multi-subunit
complexes, lipid incorporation into the organelle, mitochondrial fission and
fusion mechanisms, the role of mitochondrial nucleoids and the mtDNA
transcription factors TFB1M and TFB2M, as well as the control of PGC-1
expression. Continued study in this area will undoubtedly reveal the existence
of other important mechanisms involved in regulating mitochondrial biogenesis
in health, disease and as a result of exercise. This will also have
implications for our understanding of mitochondrial dysfunction following
skeletal muscle disuse or as a result of disease.
List of abbreviations
BB inhibitor
BB
coactivator-1
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) is associated with the
production of reactive oxygen species (ROS) from within the ETC, both of which
can be reduced by the activity of uncoupling protein-3 (UCP3). Elevated ROS
levels can trigger the opening of the mitochondrial permeability transition
pore (mtPTP) and the release of the pro-apoptotic factors cytochrome
c and apoptosis-inducing factor (AIF). Liberation of these proteins
is the primary step in the mitochondrially mediated apoptotic program (5).
Execution of this program is also facilitated by the actions of p53 and its
downstream transcriptional target BAX. The anti-aging protein SIRT1 can
inhibit the p53 pathway leading to apoptosis and it is known to negatively
regulate hepatic PGC-1