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Editorial
Estrogen-Related Receptor-␥
Conductor of Muscle Angiogenesis Through Conversion of Fast- to
Slow-Twitch Fibers?
Alain-Pierre Gadeau, Jean-François Arnal
T
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issue vascularization is tightly coupled to its oxidative
capacity. This phenomenon is especially well characterized in skeletal muscle, which can be enriched in either
oxidative slow-twitch or glycolytic fast-twitch myofibers.1,2
Slow-twitch muscles are characterized by high-oxidativecapacity fatigue-resistant (type I) fibers and dense vascularity. Conversely, fast-twitch (type II) muscles have lower
oxidative capacity, with a less developed vascular network,
and are fatigue sensitive.3 Different studies have well demonstrated that nuclear receptors including peroxisome proliferator–activated receptor-[alpha) (PPAR-␣), PPAR-␦, and
estrogen-related receptor-␣ (ERR-␣), along with coregulators
PPAR-␥ coactivator-1␣ (PGC-1␣), PGC-1␤, and nuclear
receptor-interacting protein 1 (RIP140), control fatty acid
oxidation, oxidative phosphorylation, and mitochondrial biogenesis in skeletal muscle4 –10; however, the mechanisms
linking the oxidative profile of the muscle to its vasculature
remain a matter of major interest.
Ligand?
ERRγ
Angiogenic
factors
High capillarization
& Angiogenesis
AMPK
conductor
Metabolic
enzymes
performers
Slow Twitch
Figure. ERR-␥ as conductor of angiogenic and metabolic
program. ERR-␥ appears to act as the conductor for the implementation of both the oxidative metabolic and capillarization
programs, which are closely linked. It therefore represents a
powerful potential target to orchestrate ischemic muscle repair,
potentially better than the administration of individual performers
that are angiogenic factors.
muscle capillarization and expression of vascular endothelial
growth factor (VEGF).15,16 Thus, AMPK could be a performer in this alternative angiogenic pathway, but the upstream element that controls this gene was unknown.
Article, see p 1087
A large number of proangiogenic growth factors that
coordinate endothelial cell activation, proliferation, and migration and pericyte recruitment have been described in the
skeletal muscle (reviewed in Carmeliet11 and Ferrara and
Kerbel12). Whether nuclear receptors orchestrate the vascularization of aerobic muscles was unclear until recently. Two
factors, the coactivator PGC-1␣ and the AMP kinase (AMPK),
have drawn attention. PGC-1␣ is induced by hypoxia and
exercise13 and represents a potential target to stimulate
vascularization; however, PGC-1␣ knockout mice are viable,
retain oxidative muscle, and have normal vasculature.13,14
Because the intrinsic enrichment of blood flow to aerobic
muscles in the absence of exercise is unlikely to depend on
PGC-1␣ induction, the existence of an alternative regulatory
angiogenic pathway has been suspected. AMPK was shown
both to enhance running endurance in the absence of exercise
by inducing metabolic genes and to increase basal skeletal
ERR-␥: Missing Link and Major Conductor?
ERR-␥ is a constitutively active orphan nuclear receptor, and
unlike ERR-␣ and -␤, it is selectively expressed in metabolically active and highly vascularized tissues such as heart,
kidney, brain, and skeletal muscles, as well as in a variety of
tumors with hypermetabolic demand and abundant vasculature.3 It is described as a key regulator of multiple genes
linked to both fatty acid oxidation and mitochondrial biogenesis.17,18 From these data, in a previous work, Narkar et al
questioned how type I skeletal muscle inherently maintains
high oxidative and vascular capacity in the absence of
exercise.15 They found first that in skeletal muscle, ERR-␥ is
exclusively and abundantly expressed in oxidative (type I)
slow-twitch fibers. Therefore, they explored the potential of
ERR-␥ to control the intrinsic angiogenic pathway in oxidative slow-twitch muscles (Figure). For this purpose, they
produced transgenic mice overexpressing ERR-␥ (ERRGO)
in fast-twitch anaerobic type II muscle. Transgenic fibers
triggered aerobic transformation with mitochondrial biogenesis and type I fiber specification, which was associated with
a 100% increase in running endurance, all in the absence of
exercise. Concomitantly, muscles in ERRGO mice displayed
an activated angiogenic program that consisted of the secretion of proangiogenic factors and robust fiber vascularization.
These intrinsic effects of ERR-␥ did not depend on PGC-1␣
induction but were linked to activation of the metabolic
sensor AMPK.15 Therefore, ERR-␥ represents a previously
The opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association.
From the Université de Bordeaux, Cardiovascular Adaptation to Ischemia,
Pessac, France (A.-P.G.); INSERM, Cardiovascular Adaptation to Ischemia, Pessac, France (A.-P.G.); and INSERM, U1048-I2MC, Faculté de
Médecine, Université de Toulouse et Centre Hospitalier Universitaire de
Toulouse, Toulouse, France (J.-F.A.).
Correspondence to Alain-Pierre Gadeau, Université de Bordeaux,
Cardiovascular Adaptation to Ischemia, U1034, F-33600, Pessac, France.
E-mail [email protected]
(Circ Res. 2012;110:1042-1044.)
© 2012 American Heart Association, Inc.
Circulation Research is available at http://circres.ahajournals.org
DOI: 10.1161/CIRCRESAHA.112.268540
1042
Gadeau and Arnal
unrecognized determinant that specifies intrinsic vascular and
oxidative metabolic features that distinguish type I from type
II muscle.
ERR-␥: A Potential Target for Ischemic
Tissue Repair
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The ability to form new skeletal muscle capillaries in ischemic tissue is a major challenge. The concept that new blood
vessels can grow to enhance tissue perfusion is now achieving widespread acceptance.20 Therapeutic angiogenesis is
proposed as a complement or an alternative to surgical
revascularization. To date, several proangiogenic factors,
including VEGF and fibroblast growth factor, have been
tested and have demonstrated convincing efficiency in acute
and chronic experimental models21; however, clinical trials to
test VEGF or fibroblast growth factor angiogenic therapy in
coronary and peripheral artery diseases were disappointing
because their effects were inconsistent.21,22 One of the explanations for the lack of efficiency of angiogenic therapy
probably comes from the use of individual factors, whereas
angiogenesis is known to involve a plethora of angiogenic
factors.
On the basis of their previous data, Matsakas et al19
propose in this issue of Circulation Research a new and very
interesting approach to treat muscle ischemia, taking advantage of the ability of oxidative muscle fibers to secrete a
cocktail of angiogenic factors and thus allow recruitment of
new blood vessels. This innovative approach takes into
account the major physiological implication between metabolic characteristics of the muscle fibers and their capillarization, ie, the perfect matching between metabolic demand
and energy supply. As expected, the increased number of
oxidative fibers in ERRGO mice was associated with a strong
acceleration of the recovery of blood perfusion and the
promotion of a striking recovery from ischemic damage
compared with wild-type mice.
Moreover, they provide additional evidence that the receptor is dispensable for the classic hypoxic response of VEGFa
induction. The beneficial effect of ERR-␥ in this model of
limb ischemia is linked to the receptor-mediated transformation of the transgenic skeletal muscle to one that inherently
expresses high levels of proangiogenic factors. Because
ERR-␥ is highly expressed in highly vascularized organs that
are often prone to ischemia, such as skeletal muscle, heart,
brain, and kidney, targeting ERR-␥ to potentiate and orchestrate a reparative angiogenesis of ischemic muscle would be
very powerful.
It remains to be determined to what extent these mechanisms that led to this spectacular effect in an acute ischemic
model performed in normal mice are operative in animal
models with metabolic or cardiovascular risk factors or
diseases. In addition, it is not known to what extent this
approach can provide a therapeutic benefit in chronic and
complex pathophysiological clinical conditions, such as
found in arthritic, diabetic, or elderly patients. The ischemic
tissues of these patients are characterized by an impairment of
many pathways and functions, including activation of the
hypoxia-inducible factor-1␣–VEGFa pathway23 and endothelial function.24 Furthermore, the consequence of limb immo-
Proangiogenic Role of Type I Muscular Fibers
1043
bilization (in a plaster cast, for instance) is a switch of
glycolytic fast-twitch myofibers to oxidative slow twitch, and
the muscles of diseased patients could already have shifted
toward a prominent oxidative slow twitch. Finally, even
though nuclear receptors have proved to be major pharmaceutical targets, natural ligands or synthetic drugs that activate ERR-␥ are still unknown, but studies should be conducted to search for such agents.
Disclosures
None.
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KEY WORDS: muscle fibers
䡲 ischemia
䡲
muscle
䡲
angiogenesis
䡲
nuclear receptors
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Estrogen-Related Receptor-γ: Conductor of Muscle Angiogenesis Through Conversion of
Fast- to Slow-Twitch Fibers?
Alain-Pierre Gadeau and Jean-François Arnal
Downloaded from http://circres.ahajournals.org/ by guest on June 18, 2017
Circ Res. 2012;110:1042-1044
doi: 10.1161/CIRCRESAHA.112.268540
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Copyright © 2012 American Heart Association, Inc. All rights reserved.
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