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Aging-dependent mitochondrial bioenergetic impairment in the skeletal muscle of NNT-deficient mice

Navarro, Claudia D.C. ; Francisco, Annelise LU ; Costa, Ericka F.D. ; Dalla Costa, Ana P. ; Sartori, Marina R. ; Bizerra, Paulo F.V. ; Salgado, Andréia R. ; Figueira, Tiago R. ; Vercesi, Anibal E. and Castilho, Roger F. (2024) In Experimental Gerontology 193.
Abstract

Overall health relies on features of skeletal muscle that generally decline with age, partly due to mechanisms associated with mitochondrial redox imbalance and bioenergetic dysfunction. Previously, aged mice genetically devoid of the mitochondrial NAD(P)+ transhydrogenase (NNT, encoded by the nicotinamide nucleotide transhydrogenase gene), an enzyme involved in mitochondrial NADPH supply, were shown to exhibit deficits in locomotor behavior. Here, by using young, middle-aged, and older NNT-deficient (Nnt−/−) mice and age-matched controls (Nnt+/+), we aimed to investigate how muscle bioenergetic function and motor performance are affected by NNT expression and aging. Mice were subjected to the wire-hang... (More)

Overall health relies on features of skeletal muscle that generally decline with age, partly due to mechanisms associated with mitochondrial redox imbalance and bioenergetic dysfunction. Previously, aged mice genetically devoid of the mitochondrial NAD(P)+ transhydrogenase (NNT, encoded by the nicotinamide nucleotide transhydrogenase gene), an enzyme involved in mitochondrial NADPH supply, were shown to exhibit deficits in locomotor behavior. Here, by using young, middle-aged, and older NNT-deficient (Nnt−/−) mice and age-matched controls (Nnt+/+), we aimed to investigate how muscle bioenergetic function and motor performance are affected by NNT expression and aging. Mice were subjected to the wire-hang test to assess locomotor performance, while mitochondrial bioenergetics was evaluated in fiber bundles from the soleus, vastus lateralis and plantaris muscles. An age-related decrease in the average wire-hang score was observed in middle-aged and older Nnt−/− mice compared to age-matched controls. Although respiratory rates in the soleus, vastus lateralis and plantaris muscles did not significantly differ between the genotypes in young mice, the rates of oxygen consumption did decrease in the soleus and vastus lateralis muscles of middle-aged and older Nnt−/− mice. Notably, the soleus, which exhibited the highest NNT expression level, was the muscle most affected by aging, and NNT loss. Additionally, histology of the soleus fibers revealed increased numbers of centralized nuclei in older Nnt−/− mice, indicating abnormal morphology. In summary, our findings suggest that NNT expression deficiency causes locomotor impairments and muscle dysfunction during aging in mice.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Age-related muscle dysfunction, Locomotor impairment, Mitochondrial bioenergetics, Nicotinamide nucleotide transhydrogenase, NNT deficiency, Oxidative stress
in
Experimental Gerontology
volume
193
article number
112465
publisher
Elsevier
external identifiers
  • scopus:85193927858
  • pmid:38795789
ISSN
0531-5565
DOI
10.1016/j.exger.2024.112465
language
English
LU publication?
yes
id
5490068e-a501-451d-8e5b-878232f8bca0
date added to LUP
2024-05-31 10:31:56
date last changed
2024-06-14 11:26:39
@article{5490068e-a501-451d-8e5b-878232f8bca0,
  abstract     = {{<p>Overall health relies on features of skeletal muscle that generally decline with age, partly due to mechanisms associated with mitochondrial redox imbalance and bioenergetic dysfunction. Previously, aged mice genetically devoid of the mitochondrial NAD(P)<sup>+</sup> transhydrogenase (NNT, encoded by the nicotinamide nucleotide transhydrogenase gene), an enzyme involved in mitochondrial NADPH supply, were shown to exhibit deficits in locomotor behavior. Here, by using young, middle-aged, and older NNT-deficient (Nnt<sup>−/−</sup>) mice and age-matched controls (Nnt<sup>+/+</sup>), we aimed to investigate how muscle bioenergetic function and motor performance are affected by NNT expression and aging. Mice were subjected to the wire-hang test to assess locomotor performance, while mitochondrial bioenergetics was evaluated in fiber bundles from the soleus, vastus lateralis and plantaris muscles. An age-related decrease in the average wire-hang score was observed in middle-aged and older Nnt<sup>−/−</sup> mice compared to age-matched controls. Although respiratory rates in the soleus, vastus lateralis and plantaris muscles did not significantly differ between the genotypes in young mice, the rates of oxygen consumption did decrease in the soleus and vastus lateralis muscles of middle-aged and older Nnt<sup>−/−</sup> mice. Notably, the soleus, which exhibited the highest NNT expression level, was the muscle most affected by aging, and NNT loss. Additionally, histology of the soleus fibers revealed increased numbers of centralized nuclei in older Nnt<sup>−/−</sup> mice, indicating abnormal morphology. In summary, our findings suggest that NNT expression deficiency causes locomotor impairments and muscle dysfunction during aging in mice.</p>}},
  author       = {{Navarro, Claudia D.C. and Francisco, Annelise and Costa, Ericka F.D. and Dalla Costa, Ana P. and Sartori, Marina R. and Bizerra, Paulo F.V. and Salgado, Andréia R. and Figueira, Tiago R. and Vercesi, Anibal E. and Castilho, Roger F.}},
  issn         = {{0531-5565}},
  keywords     = {{Age-related muscle dysfunction; Locomotor impairment; Mitochondrial bioenergetics; Nicotinamide nucleotide transhydrogenase; NNT deficiency; Oxidative stress}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{Experimental Gerontology}},
  title        = {{Aging-dependent mitochondrial bioenergetic impairment in the skeletal muscle of NNT-deficient mice}},
  url          = {{http://dx.doi.org/10.1016/j.exger.2024.112465}},
  doi          = {{10.1016/j.exger.2024.112465}},
  volume       = {{193}},
  year         = {{2024}},
}