24Frailty is a geriatric syndrome characterized by increased susceptibility to adverse health 25 outcomes. One major determinant thereof is the gradual weakening of the musculoskeletal 26 system and the associated osteosarcopenia. To improve our understanding of the underlying 27 pathophysiology and, more importantly, to test potential interventions aimed at counteracting 28 frailty suitable animal models are needed. Here, we report the relevance of a mouse model of 29 accelerated aging (PolgA (D257A/D257A) ) as a model for frailty and osteosarcopenia. The 30 longitudinal assessment of the clinical mouse frailty index showed that PolgA (D257A/D257A) mice 31 accumulated health deficits at a higher rate compared to wild type littermates (PolgA (+/+) , WT). 32 Concomitantly, PolgA (D257A/D257A) mice displayed progressive musculoskeletal deterioration 33 such as reduced bone and muscle mass as well as impaired functionality thereof. Specifically, 34 PolgA (D257A/D257A) had lower grip-strength and concentric muscle forces as well as reduced bone 35 turnover as assessed by longitudinal micro-CT. In addition, PolgA (D257A/D257A) mutation altered 36 the sensitivity to anabolic stimuli in skeletal muscle, muscle progenitors and bone. While, 37 compared to WT, PolgA (D257A/D257A) caudal vertebrae were not responsive to a cyclic loading 38 regime, PolgA (D257A/D257A) muscles were hypersensitive to eccentric contractions as well as 39 leucine administration, shown by larger downstream signaling response of the mechanistic target 40 of rapamycin complex 1 (mTORC1). However, myogenic progenitors cultured in vitro showed 41 severe anabolic resistance to leucine and robust impairments in cell proliferation. Overall, 42 PolgA (D257A/D257A) mutation leads to hallmarks of age-related frailty and osteosarcopenia as 43 observed in humans and thus, provides a powerful model to better understand the relationship 44 between frailty and the aging musculoskeletal system. 45 86exhibits an accelerated aging phenotype (38, 39), as a model of frailty and osteosarcopenia.
87While these mice are known to develop multiple signs of aging (e.g., hair loss, greying, hearing 88 loss) earlier (around 40 weeks of age) than their wild type littermates (PolgA +/+ , referred to as 89 WT), the frailty phenotype has to the best of our knowledge not yet been assessed in these mice.
90Furthermore, although several studies have reported lower muscle weights in PolgA mice 91 compared to their WT littermates (38, 40, 41), little is known about their muscle quality and 92 functionality. To address this, forelimb grip-strength and concentric muscle forces were 93 measured in vivo and ex vivo, respectively, in addition to the evaluation of hind limb muscles 94 masses. With respect to the bone phenotype, only two studies have reported reduced femoral 95 5 bone density using X-ray densitometry (38, 39). Although this technique is still the gold-96 standard to assess bone mineral density (i.e. bone quantity) clinically in humans, it does not 97 provide insight regard...
