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Skeletal muscle ATP kinetics are impaired in frail mice

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Abstract

The interleukin-10 knockout mouse (IL10tm/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 31P 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 (Pi) in hind limb SM of 92-week-old control (n = 7) and IL10tm/tm (n = 6) mice. SM Phosphocreatine (20.2 ± 2.3 vs. 16.8 ± 2.3 μmol/g, control vs. IL10tm/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 (Pi → ATP) (0.58 ± 0.3 vs. 0.26 ± 0.2 μmol/g/s, p < 0.05) and the free energy released from ATP hydrolysis (∆G ∼ATP) were significantly lower and [Pi] (2.8 ± 1.0 vs. 5.3 ± 2.0 μmol/g, control vs. IL10tm/tm, p < 0.05) markedly higher in IL10tm/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.

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Authors and Affiliations

  1. Cardiology Division, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Ashwin Akki, Ashish Gupta, Michelle K. Leppo & Robert G. Weiss

  2. Division of Magnetic Resonance Research, Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Ashwin Akki, Ashish Gupta, Vadappuram P. Chacko & Robert G. Weiss

  3. Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Huanle Yang & Jeremy Walston

  4. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Toshiyuki Yano & Charles Steenbergen

  5. The Johns Hopkins Hospital, Blalock 544, 600 N. Wolfe Street, Baltimore, MD, 21287-6568, USA

    Robert G. Weiss

Authors
  1. Ashwin Akki
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  2. Huanle Yang
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  3. Ashish Gupta
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  4. Vadappuram P. Chacko
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  5. Toshiyuki Yano
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  6. Michelle K. Leppo
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  7. Charles Steenbergen
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  8. Jeremy Walston
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  9. Robert G. Weiss
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Correspondence to Robert G. Weiss.

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Akki, A., Yang, H., Gupta, A. et al. Skeletal muscle ATP kinetics are impaired in frail mice. AGE 36, 21–30 (2014). https://doi.org/10.1007/s11357-013-9540-0

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  • DOI: https://doi.org/10.1007/s11357-013-9540-0

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