Abstract
BackgroundFrailty 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.MethodsTo evaluate the relevance of prematurely aged PolgA(D257A/D257A) mice as a model for frailty and osteosarcopenia, we quantified the clinical mouse frailty index in PolgA(D257A/D257A) and wild‐type littermates (PolgA(+/+), WT) with age and concertedly assessed the quantity and quality of bone and muscle tissue. Lastly, the anabolic responsiveness of skeletal muscle, muscle progenitors, and bone was assessed.ResultsPolgA(D257A/D257A) accumulated health deficits at a higher rate compared with WT, resulting in a higher frailty index at 40 and 46 weeks of age (+166%, +278%, P < 0.0001), respectively, with no differences between genotypes at 34 weeks. Concomitantly, PolgA(D257A/D257A) displayed progressive musculoskeletal deterioration such as reduced bone and muscle mass as well as impaired functionality thereof. In addition to lower muscle weights (−14%, P < 0.05, −23%, P < 0.0001) and fibre area (−20%, P < 0.05, −22%, P < 0.0001) at 40 and 46 weeks, respectively, PolgA(D257A/D257A) showed impairments in grip strength and concentric muscle forces (P < 0.05). PolgA(D257A/D257A) mutation altered the acute response to various anabolic stimuli in skeletal muscle and muscle progenitors. While PolgA(D257A/D257A) muscles were hypersensitive to eccentric contractions as well as leucine administration, shown by larger downstream signalling response of the mechanistic target of rapamycin complex 1, myogenic progenitors cultured in vitro showed severe anabolic resistance to leucine and robust impairments in cell proliferation. Longitudinal micro‐computed tomography analysis of the sixth caudal vertebrae showed that PolgA(D257A/D257A) had lower bone morphometric parameters (e.g. bone volume fraction, trabecular, and cortical thickness, P < 0.05) as well as reduced remodelling activities (e.g. bone formation and resorption rate, P < 0.05) compared with WT. When subjected to 4 weeks of cyclic loading, young but not aged PolgA(D257A/D257A) caudal vertebrae showed load‐induced bone adaptation, suggesting reduced mechanosensitivity with age.ConclusionsPolgA(D257A/D257A) mutation leads to hallmarks of age‐related frailty and osteosarcopenia and provides a powerful model to better understand the relationship between frailty and the aging musculoskeletal system.
Highlights
There is no universally accepted definition of frailty,[1] it is considered as an age-related syndrome characterized by the decline of multiple physiological functions, leading to the accumulation of health deficits and a higher vulnerability to adverse health outcomes such as morbidity and mortality.[2]
PolgA(D257A/D257A) mutation leads to hallmarks of age-related frailty and osteosarcopenia and provides a powerful model to better understand the relationship between frailty and the aging musculoskeletal system
In the field of muscle physiology, studies in humans and rodents have shown that aged muscles are less responsive to well-known anabolic stimuli such as amino acids[10,11,12] and muscle contractions[13]; this phenomenon, termed ‘anabolic resistance’, likely results from reduced protein synthesis due to diminished intracellular signalling through the mechanistic target of rapamycin complex 1 pathway.[14,15,16]
Summary
There is no universally accepted definition of frailty,[1] it is considered as an age-related syndrome characterized by the decline of multiple physiological functions, leading to the accumulation of health deficits and a higher vulnerability to adverse health outcomes such as morbidity and mortality.[2]. In the field of muscle physiology, studies in humans and rodents have shown that aged muscles are less responsive to well-known anabolic stimuli such as amino acids[10,11,12] and muscle contractions[13]; this phenomenon, termed ‘anabolic resistance’, likely results from reduced protein synthesis due to diminished intracellular signalling through the mechanistic target of rapamycin complex 1 (mTORC1) pathway.[14,15,16] Next to impairments in intramuscular mTORC1 signalling, age-related sarcopenia has been associated with a decrease in number[17,18] and proliferation capacity[19,20] of myogenic progenitors or satellite cells These are instrumental for the maintenance of muscle fibres, and for the adaptive responses to exercise and regeneration upon injury.[21] In the field of bone physiology, evidence pointing towards altered mechanosensitivity with age has been shown in humans[22] and in mice.[23,24,25,26] this effect might be site specific as studies using a tibia-loading model showed a reduced response of trabecular[23,24] and cortical[25,26] bone formation with age, while bone adaptation in response to loading of the caudal vertebrae was maintained with age.[27]. To improve our understanding of the underlying pathophysiology and, more importantly, to test potential interventions aimed at counteracting frailty, suitable animal models are needed
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