More muscle, less fat, improved endurance... it all sounds good, what's the catch?
Drug Candidate Designed at Scripps Research Institute Leads to Improved Endurance
JUPITER, FL, July 14, 2013 – An international group of scientists has shown that a drug candidate designed by scientists from the Florida campus of The Scripps Research Institute (TSRI) significantly increases exercise endurance in animal models.
These findings could lead to new approaches to helping people with conditions that acutely limit exercise tolerance, such as obesity, chronic obstructive pulmonary disease (COPD) and congestive heart failure, as well as the decline of muscle capacity associated with aging.
The study was published July 14, 2013, by the journal Nature Medicine.
The drug candidate, SR9009, is one of a pair of compounds developed in the laboratory of TSRI Professor Thomas Burris and described in a March 2012 issue of the journal Nature as reducing obesity in animal models. The compounds affect the core biological clock, which synchronizes the rhythm of the body’s activity with the 24-hour cycle of day and night.
The compounds work by binding to one of the body’s natural molecules called Rev-erbα, which influences lipid and glucose metabolism in the liver, the production of fat-storing cells and the response of macrophages (cells that remove dying or dead cells) during inflammation.
In the new study, a team led by scientists at the Institut Pasteur de Lille in France demonstrated that mice lacking Rev-erbα had decreased skeletal muscle metabolic activity and running capacity. Burris’ group showed that activation of Rev-erbα with SR9009 led to increased metabolic activity in skeletal muscle in both culture and in mice. The treated mice had a 50 percent increase in running capacity, measured by both time and distance.
“The animals actually get muscles like an athlete who has been training,” said Burris. “The pattern of gene expression after treatment with SR9009 is that of an oxidative-type muscle— again, just like an athlete.”
The authors of the new study suggest that Rev-erbα affects muscle cells by promoting both the creation of new mitochondria (often referred to as the “power plants” of the cell) and the clearance of those mitochondria that are defective.
The study, “Rev-Erbα Modulates Skeletal Muscle Oxidative Capacity by Regulating Mitochondrial Biogenesis and Autophagy” was led by Estelle Woldt and Yasmine Sebti (first authors) and Bart Staels and Hélène Duez (senior authors) of Institut Pasteur de Lille, France. Other contributors include Christian Duhem, Jérôme Eeckhoute, Charlotte Paquet, Stéphane Delhaye and Philippe Lefebvre of Institut Pasteur de Lille, France; Laura Solt, Youseung Shin, Thomas Burris and Theodore M. Kamenecka of TSRI; Steve Lancel and Rémi Nevière of Université Lille Nord de France; and Matthijs K.C. Hesselink, Gert Schaart and Patrick Schrauwen of Maastricht University Medical Center, Maastricht, the Netherlands.
The study was supported by a Marie Curie International Reintegration Grant (FP7), the European Commission (FP7) consortium Eurhythdia, Région Nord Pas-de-Calais/FEDER, a CPER “starting grant,” the European Genomic Institute for Diabetes (ANR-10-LABX-46), an unrestricted ITMO/Astra Zeneca grant, a joint Société Francophone du Diabète MSD research fellowship, Research Grant from the European Foundation for the Study of Diabetes, National Institutes of Health grant (MH093429 and DK080201) and a VICI Research grant for innovative research from the Netherlands Organization for Scientific Research (918.96.618).
http://www.scripps.e...729/burris.html
Here is the abstract:
1. Nat Med. 2013 Aug;19(8):1039-46. doi: 10.1038/nm.3213. Epub 2013 Jul 14.
Rev-erb-α modulates skeletal muscle oxidative capacity by regulating
mitochondrial biogenesis and autophagy.
Woldt E, Sebti Y, Solt LA, Duhem C, Lancel S, Eeckhoute J, Hesselink MK, Paquet
C, Delhaye S, Shin Y, Kamenecka TM, Schaart G, Lefebvre P, Nevière R, Burris TP,
Schrauwen P, Staels B, Duez H.
1] Institut Pasteur de Lille, Lille, France. [2] Institut National de la Santé et
de la Recherche Médicale Unité Mixte de Recherche 1011 'Nuclear Receptors,
Cardiovascular Diseases and Diabetes', Lille, France. [3] Faculté des Sciences
Pharmaceutiques et Biologiques et Faculté de Médecine, Université Lille Nord de
France, Lille, France. [4] Université du Droit et de la Santé de Lille, Lille,
France. [5] European Genomic Institute for Diabetes, Lille, France. [6].
The nuclear receptor Rev-erb-α modulates hepatic lipid and glucose metabolism,
adipogenesis and the inflammatory response in macrophages. We show here that
Rev-erb-α is highly expressed in oxidative skeletal muscle and that its
deficiency in muscle leads to reduced mitochondrial content and oxidative
function, as well as upregulation of autophagy. These cellular effects resulted
in both impaired mitochondrial biogenesis and increased clearance of this
organelle, leading to compromised exercise capacity. On a molecular level,
Rev-erb-α deficiency resulted in deactivation of the Lkb1-Ampk-Sirt1-Ppargc-1α
signaling pathway. These effects were recapitulated in isolated fibers and in
muscle cells after knockdown of the gene encoding Rev-erb-α, Nr1d1. In
complementary experiments, Rev-erb-α overexpression in vitro increased the number
of mitochondria and improved respiratory capacity, whereas muscle overexpression
or pharmacological activation of Rev-erb-α in vivo increased exercise capacity.
This study identifies Rev-erb-α as a pharmacological target that improves muscle
oxidative function by modulating gene networks controlling mitochondrial number
and function.
PMCID: PMC3737409 [Available on 2014/2/1]
PMID: 23852339 [PubMed - in process]
http://www.ncbi.nlm....pubmed/23852339
And you can purchase the compound:
http://www.millipore...df-1032-1302-RC
But it may not be that simple: upregulating Rev-erb-α may not work the same in everyone, because of polymorphisms, some of which are associated with obesity risk:
1. Int J Obes (Lond). 2013 May;37(5):666-72. doi: 10.1038/ijo.2012.117. Epub 2012
Jul 17.
Impact of REV-ERB alpha gene polymorphisms on obesity phenotypes in adult and
adolescent samples.
Goumidi L, Grechez A, Dumont J, Cottel D, Kafatos A, Moreno LA, Molnar D,
Moschonis G, Gottrand F, Huybrechts I, Dallongeville J, Amouyel P, Delaunay F,
Meirhaeghe A.
INSERM, U744, Institut Pasteur de Lille, Univ Lille Nord de France, UDSL, Lille,
France.
BACKGROUND: REV-ERBα has been shown to regulate adipogenesis and lipid metabolism
as well as to link the circadian timing system to whole body metabolic
homeostasis. We thus tested whether polymorphisms in REV-ERBα could be associated
with metabolic phenotypes in human population samples.
METHODS: We analyzed the associations between 5 REV-ERBα polymorphisms and
anthropometric (body weight, body mass index (BMI), waist and hip
circumferences), biochemical (plasma lipid, glucose and insulin levels) and
clinical (systolic and diastolic blood pressure) variables in three
population-based studies (MONICA Lille n=1155 adults, MONA LISA Lille n=1170
adults and HELENA n=1155 adolescents). We assessed in vitro, the potential
influence of one REV-ERBα polymorphism in transient transfection assays using two
different cell lines.
RESULTS: We observed significant and consistent associations between the T minor
allele of the REV-ERBα rs2071427 polymorphism (located in intron 1) and higher
BMI (mean allele effect=+0.33 kg m(-2)) in the MONICA Lille (P=0.02), MONA LISA
(P=0.02) and HELENA (P=0.03) studies. The odds ratios for obesity associated with
this allele were 1.67 (1.00-2.79) (P=0.05) in MONICA Lille, 1.29 (1.01-1.65)
(P=0.04) in MONA LISA Lille and the odds ratio for overweight was 1.48
(1.08-2.03) (P=0.01) in HELENA. In transfection experiments in human
hepatocyte-derived cell lines, the REV-ERBα intron 1 directed the transcription
of a luciferase reporter gene independently of the rs2071427 polymorphism.
CONCLUSION: Our results suggest that the REV-ERBα rs2071427 polymorphism
modulates body fat mass in both adult and young people.
PMID: 22828941 [PubMed - in process]
http://www.ncbi.nlm....pubmed/22828941
Rev-erb-α also may modulate immune function, and maybe not in a good way?
http://www.ncbi.nlm....pubmed/23728303
And it may regulate circadian rhythms.
http://www.ncbi.nlm....pubmed/22460951
Can anyone access the full article? I just get a blank page when I try:
http://www.nature.co...ll/nm.3213.html
I am curious to know how the mice were treated, what dosages and what other effects were observed.
