A soluble activin receptor type IIb prevents the effects of androgen deprivation on body composition and bone health.
Androgen deprivation, a consequence of hypogonadism, certain cancer treatments, or normal aging in men, leads to loss of muscle mass, increased adiposity, and osteoporosis. In the present study, using a soluble chimeric form of activin receptor type IIB (ActRIIB) we sought to offset the adverse effects of androgen deprivation on muscle, adipose tissue, and bone. Castrated (ORX) or sham-operated (SHAM) mice received either TBS [vehicle-treated (VEH)] or systemic administration of ActRIIB-mFc, a soluble fusion protein comprised of a form of the extracellular domain of ActRIIB fused to a murine IgG2aFc subunit. In vivo body composition imaging demonstrated that ActRIIB-mFc treatment results in increased lean tissue mass of 23% in SHAM mice [19.02 +/- 0.42 g (VEH) versus 23.43 +/- 0.35 g (ActRIIB-mFc), P < 0.00001] and 26% in ORX mice [15.59 +/- 0.26 g (VEH) versus 19.78 +/- 0.26 g (ActRIIB-mFc), P < 0.00001]. Treatment also caused a decrease in adiposity of 30% in SHAM mice [5.03 +/- 0.48 g (VEH) versus 3.53 +/- 0.19 g (ActRIIB-mFc), NS] and 36% in ORX mice [7.12 +/- 0.53 g (VEH) versus 4.57 +/- 0.28 g (ActRIIB-mFc), P < 0.001]. These changes were also accompanied by altered serum levels of leptin, adiponectin, and insulin, as well as by prevention of steatosis (fatty liver) in ActRIIB-mFc-treated ORX mice. Finally, ActRIIB-mFc prevented loss of bone mass in ORX mice as assessed by whole body dual x-ray absorptiometry and micro-computed tomography of proximal tibias. The data demonstrate that treatment with ActRIIB-mFc restored muscle mass, adiposity, and bone quality to normal levels in a mouse model of androgen deprivation, thereby alleviating multiple adverse consequences of such therapy.
Koncarevic
Alan
A
Acceleron Pharma, Inc., Cambridge, Massachusetts 02139, USA.
Cornwall-Brady
Milton
M
Pullen
Abigail
A
Davies
Monique
M
Sako
Dianne
D
Liu
June
J
Kumar
Ravindra
R
Tomkinson
Kathleen
K
Baker
Theresa
T
Umiker
Ben
B
Monnell
Travis
T
Grinberg
Asya V
AV
Liharska
Katia
K
Underwood
Kathryn W
KW
Ucran
Jeffrey A
JA
Howard
Elizabeth
E
Barberio
Joseph
J
Spaits
Matthew
M
Pearsall
Scott
S
Seehra
Jasbir
J
Lachey
Jennifer
J
D030301:Activin Receptors, Type II / Q000235:genetics / Q000494:pharmacology*; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000704:Analysis of Variance; D000726:Androgen Antagonists / Q000494:pharmacology*; D000818:Animals; D001823:Body Composition / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects*; D002460:Cell Line; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D007074:Immunoglobulin G / Q000235:genetics; D020738:Leptin / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000097:blood / Q000517:prevention & control; D009919:Orchiectomy; D011897:Random Allocation; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D012995:Solubility
D000726:Androgen Antagonists; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D020738:Leptin; D011993:Recombinant Fusion Proteins; D030301:Activin Receptors, Type II; C425584:activin receptor type II-B