Sarcopenia and Increased Body Fat in Sclerostin-deficient Mice: Interactions between Muscle and Bone and Potential Implications for Osteoporosis Management

In the absence of mechanical load (off-loading), as may occur following injury, bone and muscle tissue are lost, increasing the risk of low-impact bone fracture and musculoskeletal weakness and injury. Henry J. Donahue, Ph.D., Michael and Myrtle Baker Professor of Orthopaedics at Penn State College of Medicine, observes, “While bone loss following disuse is fairly well-understood, relatively little is known about how bone and muscle tissues interact during off-loading.”

Sclerostin [a glycoprotein encoded by the SOST gene that inhibits the Wnt signaling pathway], a key factor that mediates bone loss, exhibits increased expression by osteocytes during off-loading and inhibits bone formation by osteoblasts. Donahue, and anatomy graduate student Andrew Krause, along with Charles Lang, Ph.D., distinguished professor of cellular and molecular physiology, conducted an experiment in SOST-knockout mice, globally deficient in sclerostin, and subjected to off-loading, to examine effects on muscle tissue, as well as bone. Donahue explains, “In the SOST-knockout mice, as we predicted, trabecular bone loss from two weeks of off-loading was largely mitigated, compared to the loss seen in wild-type mice. What was interesting and unexpected was that at baseline, even though both groups of mice were of similar weight, the sclerostin-deficient mice had significantly less lean muscle tissue and more adipose tissue; off-loading led to further and dramatic loss of muscle [e.g., sarcopenia] and gain of fat.” (see figure)

Osteoporosis Management

Sclerostin-deficient mice (right) have bigger bone than normal wild type mice (left). However, muscle mass actually decreases in sclerostin-deficient mice.

The research demonstrates that signaling pathways, underlying bone formation, and resorption also impact and interact with other pathways involved in muscle and adipose tissue. Currently, anti-sclerostin antibodies are being developed for potential clinical use in the treatment of osteoporosis. Donahue notes that his group’s findings in sclerostin-deficient mice could have important clinical implications for patients.

“Our data raise the possibility that sarcopenia may be a potential complication in patients treated over the long-term with anti-sclerostin antibody. Right now, there are no clinical data to suggest that this happens, but it’s a possibility that deserves to be examined. In older adults, muscle tissue loss occurs as a normal part of aging. So a further reduction in muscle that might occur secondary to anti-sclerostin treatment could increase the risk of injury or other problems associated with sarcopenia,” says Donahue.

Donahue’s research program is supported by grants from the National Space Biological Research Institute, a partner of the National Aeronautics and Space Administration (NASA), and is aimed at exploring the interaction of bone and muscle physiology in microgravity environments. The findings were presented at the September meeting of the American Society of Bone and Mineral Research where Krause won “Best Abstract” for a young investigator.


DonahueHenryHenry J. Donahue, Ph.D.
Michael and Myrtle Baker Professor of Orthopaedics
Vice Chair for Research and Director, Division of Musculoskeletal Sciences
Department of Orthopaedics and Rehabilitation
Professor, Biomedical Engineering and Cellular and Molecular Physiology
Phone: 717-531-4819
E-mail: hdonahue@hmc.psu.edu
Postdoctoral Training: Mayo Graduate School of Medicine, Rochester, Minnesota
Graduate Study: Ph.D., biological sciences, University of California, Santa Barbara, California


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