Microbial-derived Exerkines preserve muscle size and function during disuse in aged mice in a sex-dependent manner

Disuse-induced muscle atrophy is a critical clinical challenge in older adults. Existing countermeasures have largely failed to preserve muscle size and function, underscoring the need for novel therapeutic strategies. We recently identified pipecolic acid and succinate (PAS) as microbial-derived exerkines that prevent disuse-induced atrophy and preserve muscle function in adult mice. Here, we tested whether PAS similarly protects aged muscle. Aged male and female mice received vehicle (VEH) or PAS via drinking water during 10 days of unilateral hindlimb casting. PAS did not preserve soleus or plantaris mass, but casted gastrocnemius mass was greater in PAS- than VEH-treated mice irrespective of sex. PAS attenuated the loss of soleus and plantaris fiber cross-sectional area, with the largest effect in the female soleus. PAS enhanced soleus contractile function in a sex-specific manner: females exhibited greater absolute force and rate of force development, and males greater fatigue resistance. Gastrocnemius citrate synthase activity was greater in PAS- than VEH-treated females but not males, mirroring the female-specific preservation of soleus fiber size and function. These sexually dimorphic responses highlight microbial-derived metabolites as a novel therapeutic avenue for preserving muscle function during disuse in aging and underscore the importance of considering sex as a biological variable.