The Physical and Biological Characterization of a Frail Mouse Model

Walston, Jeremy D.; Fedarko, Neal S.; Yang, Hongdian; Leng, Sean X.; Beamer, Brock A.; Espinoza, Sara; Lipton, Anne M.; Zheng, Howie; Becker, K evin G.

doi:10.1093/gerona/63.4.391

Cited by 171 publications

(139 citation statements)

References 22 publications

Supporting

Mentioning

136

Contrasting

Unclassified

Order By: Relevance

“…Cause–effect relationship will be important, given the result of clinical studies that found that inhibiting certain inflammatory cytokines, for example, TNF‐α, had no impact on mortality in the setting of HFrEF (Coletta et al ., 2002). Investigators have found that mice that are deficient in IL‐10, an immune suppressive cytokine, exhibit some clinical features of frailty, specifically declining muscle strength by 14 months of age as compared to age‐matched wild‐type controls (Walston et al ., 2008). This study represents a potential murine model of frailty; however, it is confounded as IL‐10‐deficient mice exhibit signs of inflammatory bowel disease (Davidson et al ., 2000), which could explain the features described in the study.…”

Section: How To Examine the Mechanisms Of Frailty Experimentallymentioning

confidence: 99%

Pathophysiology of heart failure and frailty: a common inflammatory origin?

et al. 2017

View full text Add to dashboard Cite

SummaryFrailty, a clinical syndrome that typically occurs in older adults, implies a reduced ability to tolerate biological stressors. Frailty accompanies many age‐related diseases but can also occur without overt evidence of end‐organ disease. The condition is associated with circulating inflammatory cytokines and sarcopenia, features that are shared with heart failure (HF). However, the biological underpinnings of frailty remain unclear and the interaction with HF is complex. Here, we describe the inflammatory pathophysiology that is associated with frailty and speculate that the inflammation that occurs with frailty shares common origins with HF. We discuss the limitations in investigating the pathophysiology of frailty due to few relevant experimental models. Leveraging current therapies for advanced HF and current known therapies to address frailty in humans may enable translational studies to better understand the inflammatory interactions between frailty and HF.

show abstract

Section: How To Examine the Mechanisms Of Frailty Experimentallymentioning

confidence: 99%

Pathophysiology of heart failure and frailty: a common inflammatory origin?

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Downregulation of the apoptotic pathway can reduce the decline in muscle mass and function in aged animals (Dirks & Leeuwenburgh, 2004; Marzetti et al ., 2009). Upregulation of the apoptotic pathway has been identified in premature aging models including mice lacking the antioxidant enzyme copper/zinc‐dependent superoxide dismutase (CuZnSOD or Sod1) that exhibit accelerated sarcopenia (Jang et al ., 2010), as well as interleukin‐10‐deficient mice that exhibit extreme frailty (Walston et al ., 2008). Increased levels of DNA laddering and caspase‐3 activity have been observed in transgenic mice expressing defective mitochondrial polymerase (Hiona et al ., 2010).…”

Section: Introductionmentioning

confidence: 99%

Apoptosis and necrosis mediate skeletal muscle fiber loss in age‐induced mitochondrial enzymatic abnormalities

et al. 2015

View full text Add to dashboard Cite

SummarySarcopenia, the age‐induced loss of skeletal muscle mass and function, results from the contributions of both fiber atrophy and loss of myofibers. We have previously characterized sarcopenia in FBN rats, documenting age‐dependent declines in muscle mass and fiber number along with increased fiber atrophy and fibrosis in vastus lateralis and rectus femoris muscles. Concomitant with these sarcopenic changes is an increased abundance of mitochondrial DNA deletion mutations and electron transport chain (ETC) abnormalities. In this study, we used immunohistological and histochemical approaches to define cell death pathways involved in sarcopenia. Activation of muscle cell death pathways was age‐dependent with most apoptotic and necrotic muscle fibers exhibiting ETC abnormalities. Although activation of apoptosis was a prominent feature of electron transport abnormal muscle fibers, necrosis was predominant in atrophic and broken ETC‐abnormal fibers. These data suggest that mitochondrial dysfunction is a major contributor to the activation of cell death processes in aged muscle fibers. The link between ETC abnormalities, apoptosis, fiber atrophy, and necrosis supports the hypothesis that mitochondrial DNA deletion mutations are causal in myofiber loss. These studies suggest a progression of events beginning with the generation and accumulation of a mtDNA deletion mutation, the concomitant development of ETC abnormalities, a subsequent triggering of apoptotic and, ultimately, necrotic events resulting in muscle fiber atrophy, breakage, and fiber loss.

show abstract

“…The IL10 tm/tm mice develop an age-related increase in SM weakness, inflammation and increased mortality compared to age-matched B6 mice and thus have been proposed as a model of human frailty (Walston et al 2008;Ko et al 2012). We report here, for the first time, that in vivo SM energy metabolism is deranged at rest in frail IL10 tm/tm mice as evidenced by a decline in intracellular [PCr], accumulation of P i , together with a decrease in the rate of ATP synthesis via CK (i.e., CK flux) and in the unidirectional rate of ATP synthesis from P i as compared to age-matched controls.…”

Section: Discussionmentioning

confidence: 99%

“…Ninety-two-week-old male IL-10 deficient (IL10 tm/tm ) and age-and sex-matched C57/BL6 (B6) mice were used for this study. Strength and activity decline with age in IL10 tm/tm mice, as compared to control mice, and mortality is increased at this age (Walston et al 2008;Ko et al 2012). IL10 tm/tm mice were homozygous for the IL10 tm/Cgn targeted mutation and were fully backcrossed on B6 background (Kuhn et al 1993).…”

Section: Animalsmentioning

confidence: 99%

“…Despite recent advances in frailty research in human cohorts, the mechanisms that mediate SM decline and adverse outcomes in frailty remain unclear (Kanapuru and Ershler 2009). The homozygous interleukin-10 null, B6.129P2-IL10 ™/Cgn /J (IL10 ™/™ ) mouse has been proposed as a model to study the biology linking chronic inflammation and frailty (Walston et al 2008) given that they, like frail humans, develop elevated serum interleukin-6 (IL6), muscle weakness, and higher mortality compared to age-matched C57BL/6J (B6) controls (Walston et al 2008;Ko et al 2012).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Skeletal muscle ATP kinetics are impaired in frail mice

Akki

Yang

Gupta

et al. 2013

AGE

View full text Add to dashboard Cite

The interleukin-10 knockout mouse (IL10 tm/tm ) has been proposed as a model for human frailty, a geriatric syndrome characterized by skeletal muscle (SM) weakness, because it develops an age-related decline in SM strength compared to control (C57BL/6J) mice. Compromised energy metabolism and energy deprivation appear to play a central role in muscle weakness in metabolic myopathies and muscular dystrophies. Nonetheless, it is not known whether SM energy metabolism is altered in frailty. A combination of in vivo 31 P nuclear magnetic resonance experiments and biochemical assays was used to measure high-energy phosphate concentrations, the rate of ATP synthesis via creatine kinase (CK), the primary energy reserve reaction in SM, as well as the unidirectional rates of ATP synthesis from inorganic phosphate (P i ) in hind limb SM of 92-week-old control (n=7) and IL10 tm/tm (n=6) mice. SM Phosphocreatine (20.2±2.3 vs. 16.8± 2.3 μmol/g, control vs. IL10 tm/tm , p<0.05), ATP flux via CK (5.0±0.9 vs. 3.1±1.1 μmol/g/s, p<0.01), ATP synthesis from inorganic phosphate (P i →ATP) (0.58±0.3 vs. 0.26±0.2 μmol/g/s, p<0.05) and the free energy released from ATP hydrolysis (ΔG ∼ATP ) were significantly lower and [P i ] (2.8±1.0 vs. 5.3± 2.0 μmol/g, control vs. IL10 tm/tm , p<0.05) markedly higher in IL10 tm/tm than in control mice. These observations demonstrate that, despite normal in vitro metabolic enzyme activities, in vivo SM ATP kinetics, high-energy phosphate levels and energy release from ATP hydrolysis are reduced and inorganic phosphate is elevated in a murine model of frailty. These observations do not prove, but are consistent with the premise, that energetic abnormalities may contribute metabolically to SM weakness in this geriatric syndrome.

show abstract

The Physical and Biological Characterization of a Frail Mouse Model

Cited by 171 publications

References 22 publications

Pathophysiology of heart failure and frailty: a common inflammatory origin?

Pathophysiology of heart failure and frailty: a common inflammatory origin?

Apoptosis and necrosis mediate skeletal muscle fiber loss in age‐induced mitochondrial enzymatic abnormalities

Skeletal muscle ATP kinetics are impaired in frail mice

Contact Info

Product

Resources

About