Hallmarks of frailty and osteosarcopenia in prematurely aged PolgAD257A/D257A mice: a preclinical model to test anabolic interventions

Frailty is a geriatric syndrome characterized by increased susceptibility to adverse health outcomes. One major determinant thereof is the gradual weakening of the musculoskeletal system and the associated osteosarcopenia. To improve our understanding of the underlying pathophysiology and, more importantly, to test potential interventions aimed at counteracting frailty suitable animal models are needed. Here, we report the relevance of a mouse model of accelerated aging (PolgA (D257A/D257A)) as a model for frailty and osteosarcopenia. The longitudinal assessment of the clinical mouse frailty index showed that PolgA(D257A/D257A) mice accumulated health deficits at a higher rate compared to wild type littermates (PolgA(+/+), WT). Concomitantly, PolgA(D257A/D257A) mice displayed progressive musculoskeletal deterioration such as reduced bone and muscle mass as well as impaired functionality thereof. Specifically, PolgA(D257A/D257A) had lower grip-strength and concentric muscle forces as well as reduced bone turnover as assessed by longitudinal micro-CT. In addition, PolgA(D257A/D257A) mutation altered the sensitivity to anabolic stimuli in skeletal muscle, muscle progenitors and bone. While, compared to WT, PolgA(D257A/D257A) caudal vertebrae were not responsive to a cyclic loading regime, PolgA(D257A/D257A) muscles were hypersensitive to eccentric contractions as well as leucine administration, shown by larger downstream signaling response of the mechanistic target of rapamycin complex 1 (mTORC1). However, myogenic progenitors cultured in vitro showed severe anabolic resistance to leucine and robust impairments in cell proliferation. Overall, PolgA(D257A/D257A) mutation leads to hallmarks of age-related frailty and osteosarcopenia as observed in humans and thus, provides a powerful model to better understand the relationship between frailty and the aging musculoskeletal system.