The effect of rapamycin and its analogues on age-related musculoskeletal diseases: a systematic review

Abstract

Background Preclinical studies have shown a therapeutic role of the mechanistic/mammalian target of rapamycin complex 1 (mTORC1) inhibition with rapamycin and its analogues (rapalogues) on several age-related musculoskeletal disorders (MSKD). However, the applicability to humans of these findings is unknown. Objective To assess the efficacy of rapalogues on age-related MSKD in humans. Methods We conducted a systematic review according to the PRISMA guidelines. MEDLINE, EMBase, EMCare, and Cochrane Central Registry of Controlled Trials were searched for original studies examining the effects of rapalogues on outcomes linked to the age-related MSKD in humans. This review is registered in the PROSPERO database (University of New York; registration number CRD42020208167). Results Fourteen studies met the inclusion criteria and were analyzed. The effect of rapamycin and other rapalogues, including everolimus and temsirolimus, on bone, muscle and joints have been evaluated in humans; however, considerable variability concerning the subjects’ age, inclusion criteria, and drug administration protocols was identified. In bone, the use of rapamycin is associated with a decrease in bone resorption markers dependent on osteoclastic activity. In muscle, rapamycin and rapalogues are associated with a reduction in muscle protein synthesis in response to exercise. In the context of rheumatoid arthritis, rapamycin and rapalogues have been associated with clinical improvement and a decrease in inflammatory activity. Conclusion Although there are studies that have evaluated the effect of rapamycin and rapalogues on MSKD in humans, the evidence supporting its use is still incipient, and the clinical implication of these results on the development of osteoporosis, sarcopenia, or osteosarcopenia has not been studied, opening an interesting field for future research.

Pathophysiology to Risk Factor and Therapeutics to Treatment Strategies on Epilepsy

“…Some studies have suggested that there are mechanisms in common between epilepsy and ASD, such as the hyperactivation of mTOR signaling through genetic mutations; this signaling pathway is related to the control of cell growth and was discovered based on rapamycin, which works as an inhibitor of this pathway and is used in the control of some pathologies, such as rheumatoid arthritis and atherosclerosis. A study with animal models showed that rapamycin exhibited positive results in individuals with ASD and epilepsy [186][187][188][189]. In addition to this, another relationship was observed between ASD and epilepsy, i.e., the absence or low signaling of the GABAergic marker, which causes an imbalance in the cerebral cortex of humans, as well as in animal models [187].…”

Bisphosphonates attenuate age‐related muscle decline inCaenorhabditis elegans

“…Established drugs that modify human muscle ageing are limited, and importantly, many of these drugs display variable therapeutic efficacy and associate with harmful side‐effect profiles that render them inappropriate for long‐term clinical use. For example, rapamycin holds variable efficacy against sarcopenia indices across health and disease 8 but is a potent immunosuppressant 9 unsuitable for chronic use in otherwise healthy humans. Drug identification efforts might instead focus on repurposing existing clinically approved compounds for sarcopenic indications as a realistic, immediately employable approach to therapeutic discovery.…”