Osteocalcin Signaling in Myofibers Is Necessary and Sufficient for Optimum Adaptation to Exercise.
Circulating levels of undercarboxylated and bioactive osteocalcin double during aerobic exercise at the time levels of insulin decrease. In contrast, circulating levels of osteocalcin plummet early during adulthood in mice, monkeys, and humans of both genders. Exploring these observations revealed that osteocalcin signaling in myofibers is necessary for adaptation to exercise by favoring uptake and catabolism of glucose and fatty acids, the main nutrients of myofibers. Osteocalcin signaling in myofibers also accounts for most of the exercise-induced release of interleukin-6, a myokine that promotes adaptation to exercise in part by driving the generation of bioactive osteocalcin. We further show that exogenous osteocalcin is sufficient to enhance the exercise capacity of young mice and to restore to 15-month-old mice the exercise capacity of 3-month-old mice. This study uncovers a bone-to-muscle feedforward endocrine axis that favors adaptation to exercise and can reverse the age-induced decline in exercise capacity.
Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA.
Paula
P
Mera
Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA.
Kathrin
K
Laue
Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA.
Mathieu
M
Ferron
INSERM UMR1033-Université de Lyon, Hospices Civils de Lyon, Lyon 69003, France.
Cyril
C
Confavreux
Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA.
Jianwen
J
Wei
Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, NY 10032, USA.
Marta
M
Galán-Díez
UMR 9214 CNRS, U1046 INSERM, Université de Montpellier, CHRU Montpellier, 34295 Montpellier Cedex 5, France.
Alain
A
Lacampagne
Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
Sarah J
SJ
Mitchell
Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
Julie A
JA
Mattison
Department of Medicine (Cardiology), Department of Cell Biology, and Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Yun
Y
Chen
INSERM UMR1033-Université de Lyon, Hospices Civils de Lyon, Lyon 69003, France.
Justine
J
Bacchetta
INSERM UMR1033-Université de Lyon, Hospices Civils de Lyon, Lyon 69003, France.
Pawel
P
Szulc
Department of Medicine (Cardiology), Department of Cell Biology, and Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Richard N
RN
Kitsis
Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
Rafael
R
de Cabo
Department of Biomedical Informatics, Columbia University Medical Center, New York, NY 10032, USA.
Richard A
RA
Friedman
Department of Biochemistry, Weill Medical College of Cornell University, New York, NY 10065, USA.
Christopher
C
Torsitano
Department of Biochemistry, Weill Medical College of Cornell University, New York, NY 10065, USA.
Timothy E
TE
McGraw
Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
Michelle
M
Puchowicz
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Irwin
I
Kurland
Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: gk2172@cumc.columbia.edu.
Gerard
G
Karsenty
D000222:Adaptation, Physiological; D000375:Aging / Q000378:metabolism; D000818:Animals; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D015675:Osteocalcin / Q000378:metabolism*; D010805:Physical Conditioning, Animal; D015398:Signal Transduction
D005227:Fatty Acids; D015850:Interleukin-6; D015675:Osteocalcin; D005947:Glucose