SPERMIDINE DOES NOT INFLUENCE LIMB MUSCLE MASS FOLLOWING ANDROGEN DEPLETION

Skeletal muscle atrophy increases the risk of morbidity and mortality during various pathological conditions. In males, a decrease in the production and/or bioavailability of androgens (termed hypogonadism) directly contributes to muscle atrophy during such conditions. While it is known that androgens prevent muscle atrophy, the mechanism(s) by which androgens mediate this effect are largely undefined. To identify potential androgen sensitive pathways regulating limb muscle mass, we subjected total RNA from the tibialis anterior (TA) from castrated mice and total RNA from the TA of sham mice to microarray analysis. This approach showed that androgen depletion significant altered the expression of genes involved in the polyamine metabolic pathway. The polyamines, spermidine (Spd), spermine (Spm) and their diamine precursor putrescine, are naturally occurring, polycationic alkylamines that are absolutely required for mammalian cell growth, differentiation, and survival. Accordingly, we confirmed that androgen depletion reduced muscle expression of ornithine decarboxylase (ODC1), S‐adenosylmethionine decarboxylase (AMD1), spermine oxidase (SMOX), and spermidine/spermine N‐1acetyltrasferase (SAT1), which are genes involved with polyamine biosynthesis (ODC1, AMD1) and catabolism (SMOX, SAT1). Changes in the expression of these polyamine metabolic genes following androgen depletion coincided with a preferential decrease in Spd concentration in the TA, and this reduction was strongly related to the degree of muscle atrophy induced by the androgen depletion. To assess the role of Spd in the regulation of limb muscle mass, we treated previously castrated mice with Spd in the drinking water for 8 weeks. Even though Spd treatment completely prevented the decrease in muscle Spd concentrations following androgen depletion, mass of the TA or other limb skeletal muscles was not affected. Moreover, treating previously castrated mice with nandrolone decanoate increased muscle mass and restored expression of the polyamine metabolic genes without restoring Spd values. Thus, the decrease in Spd concentration in the limb muscle following androgen depletion likely mediates processes that are independent of muscle mass regulation. Support or Funding Information NIH Grant CA204345 to (RAC) Institute for Successful Longevity to (BSG)