title: Testosterone supplementation reverses sarcopenia in aging through regulation of myostatin, c-Jun NH2-terminal kinase, Notch, and Akt signaling pathways.
abstract: Aging in rodents and humans is characterized by loss of muscle mass (sarcopenia). Testosterone supplementation increases muscle mass in healthy older men. Here, using a mouse model, we investigated the molecular mechanisms by which testosterone prevents sarcopenia and promotes muscle growth in aging. Aged mice of 22 months of age received a single sc injection of GnRH antagonist every 2 wk to suppress endogenous testosterone production and were implanted subdermally under anesthesia with 0.5 or 1.0 cm testosterone-filled implants for 2 months (n = 15/group). Young and old mice (n = 15/group), of 2 and 22 months of age, respectively, received empty implants and were used as controls. Compared with young animals, a significant (P < 0.05) increase in muscle cell apoptosis coupled with a decrease in gastrocnemius muscles weight (by 16.7%) and muscle fiber cross-sectional area, of both fast and slow fiber types, was noted in old mice. Importantly, such age-related changes were fully reversed by higher dose (1 cm) of testosterone treatment. Testosterone treatment effectively suppressed age-specific increases in oxidative stress, processed myostatin levels, activation of c-Jun NH(2)-terminal kinase, and cyclin-dependent kinase inhibitor p21 in aged muscles. Furthermore, it restored age-related decreases in glucose-6-phosphate dehydrogenase levels, phospho-Akt, and Notch signaling. These alterations were associated with satellite cell proliferation and differentiation. Collectively these results suggest involvement of multiple signal transduction pathways in sarcopenia. Testosterone reverses sarcopenia through stimulation of cellular metabolism and survival pathway together with inhibition of death pathway.
authors.affiliation: Division of Endocrinology, Charles R. Drew University, Los Angeles, California 90059, USA.
authors.forename: Ekaterina L
authors.initials: EL
authors.lastname: Kovacheva
authors.forename: Amiya P Sinha
authors.initials: AP
authors.lastname: Hikim
authors.forename: Ruoqing
authors.initials: R
authors.lastname: Shen
authors.forename: Indranil
authors.initials: I
authors.lastname: Sinha
authors.forename: Indrani
authors.initials: I
authors.lastname: Sinha-Hikim
mesh_terms: D000375:Aging / Q000187:drug effects / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004789:Enzyme Activation; D006801:Humans; D006984:Hypertrophy; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D055435:Myostatin / Q000235:genetics / Q000502:physiology*; D009929:Organ Size; D055948:Sarcopenia / Q000517:prevention & control*; D013739:Testosterone / Q000097:blood* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D055435:Myostatin; D013739:Testosterone; D048031:JNK Mitogen-Activated Protein Kinases