FP22-2 Testosterone is a vital factor in the muscle stem cell niche that promotes muscle growth in aging

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP22-Testis Biology
Translational
Sunday, June 16, 2013: 10:45 AM-11:15 AM
Presentation Start Time: 10:50 AM
Room 104 (Moscone Center)

Poster Board SUN-536
Indranil Sinha*1, Indrani Sinha-Hikim2, Rudrani Goswami2, Ruoquing Shen2, Amy J Wagers3 and Amiya P Sinha-Hikim2
1Brigham & Women's Hospital, Harvard Medical School, Boston, MA, 2Charles R. Drew University of Medicine and Science, Los Angeles, CA, 3Harvard Stem Cell Institute, Harvard University, Cambridge, MA
Background and Objective: While the role of systemic milieu in regulating the muscle stem cell fate and growth is well known, the specific systemic signals in the muscle stem cell niche that cause satellite cell activation and promote muscle regeneration and growth are still largely unknown. In a mouse model of heterochronic parabiosis, which involves the creation of a single circulation between young (Y) and old (O) mice, Notch-1 levels and skeletal muscle regeneration following injury is improved in the aged parabiont. However, the systemic factors that rejuvenate aged progenitor cells are not known. Our recent report shows that testosterone, a circulating hormone, is able to prevent sarcopenia in aging by reducing oxidative stress and reversing adverse changes in multiple pathways, including, JNK, Notch, and Akt signaling in aged skeletal muscles. This study examines if testosterone is obligatory for restoring the systemic environment that supports muscle growth in aging.

Experimental Design: To test this hypothesis, we established the following heterochronic parabioses between Y and O C57BL6 male mice of 4 and 22 months of age, respectively: 1) Y:O; 2) castrated Y:O; and 3) Castrated + testosterone-treated Y:O. A group of young and old mice received empty implants and were used as controls. Parabiotic pairings were maintained for 4 weeks prior to analysis.

Results: Serum testosterone levels were 3-fold higher in young in comparison with old mice. Compared with heterochronic parabioses with castrated young, old mice paired with testosterone-treated orchiectomized young partners had significantly elevated levels of serum testosterone. Heterochronic parabiosis to castrated young partners exhibited perturbed muscle ultrastructure, including intramyofibrillar lipid accumulation, mitochondrial swelling with broken cristae, vacuolated mitochondria, and tubular aggregation similar to aged muscles. Notably, parabiosis with castrated + testosterone-treated young mice but not with castrated young partners fully reversed the age-related changes in gastrocnemius muscle weight, muscle ultrastructure, muscle fiber cross-sectional area, and restored Notch signaling to levels seen in young controls.

Conclusions: Together, these novel findings point to a critical role of testosterone in restoring the systemic environment that favors muscle growth in aging. Undoubtedly, the identification of the testosterone-mediated rejuvenating factors in the aged niche may reveal novel therapeutic avenues for regenerative medicine using cellular-, stem cell-, and drug-based approaches.

Nothing to Disclose: IS, IS, RG, RS, AJW, APS

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Supported by a grant from the National Institutes of Health Accelerating Excellence in Translational Science grant (U54 MD007598).