Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 7 (10), e14055

Tumor Protein 53-induced Nuclear Protein 1 Deficiency Alters Mouse Gastrocnemius Muscle Function and Bioenergetics in Vivo

Affiliations

Tumor Protein 53-induced Nuclear Protein 1 Deficiency Alters Mouse Gastrocnemius Muscle Function and Bioenergetics in Vivo

Julie Warnez-Soulie et al. Physiol Rep.

Abstract

Tumor protein 53-induced nuclear protein 1 (TP53INP1) deficiency leads to oxidative stress-associated obesity and insulin resistance. Although skeletal muscle has a predominant role in the development of metabolic syndrome, the bioenergetics and functional consequences of TP53INP1 deficiency upon this tissue remain undocumented. To clarify this issue, gastrocnemius muscle mechanical performance, energy metabolism, and anatomy were investigated in TP53INP1-deficient and wild-type mice using a multidisciplinary approach implementing noninvasive multimodal-NMR techniques. TP53INP1 deficiency increased body adiposity but did not affect cytosolic oxidative stress, lipid content, and mitochondrial pool and capacity in myocyte. During a fatiguing bout of exercise, the in vivo oxidative ATP synthesis capacity was dramatically reduced in TP53INP1-deficient mice despite ADP level (the main in vivo stimulator of mitochondrial respiration) did not differ between both genotypes. Moreover, TP53INP1 deficiency did not alter fatigue resistance but paradoxically increased the contractile force, whereas there were no differences for muscle fiber-type distribution and calcium homeostasis between both genotypes. In addition, muscle proton efflux was decreased in TP53INP1-deficient mice, thereby indicating a reduced blood supply. In conclusion, TP53INP1 plays a role in muscle function and bioenergetics through oxidative capacity impairment possibly as the consequence of abnormal mitochondrial respiration regulation and/or defective blood supply.

Keywords: Insulin resistance; mitochondrial function; multimodal NMR; obesity; oxidative stress.

Conflict of interest statement

The authors have no conflicts of interest, financial or otherwise, to declare.

Figures

Figure 1
Figure 1
Morphological characteristics. Body weight (A), gastrocnemius muscle volume (B), ratio between body weight and gastrocnemius muscle volume (C), body (D) and abdominal (E) fat contents, lean mass (F), and adiposity index (G). Data are means ± SEM. *Significantly different from Tp53inp1+/+.
Figure 2
Figure 2
Gastrocnemius muscle typology. Relative distribution of myosin heavy chain (MHC) isoform proteins.
Figure 3
Figure 3
In vitro determination of metabolic contents and citrate synthase activity. Intramyocellular lipid (IMCL) (A), total glucidic (B), glycogen (C) and glucose (D) contents, and citrate synthase activity (E). Data are means ± SEM. *Significantly different from Tp53inp1+/+.
Figure 4
Figure 4
Protein content and oxidation. Gastrocnemius muscle was analyzed by immunoblotting (A) for oxidatively modified protein, STIM1, PARKIN, PINK1, PGC‐1α, VDAC1, and 4HNE (B). Data are means ± SEM. *Significantly different from Tp53inp1+/+.
Figure 5
Figure 5
Gastrocnemius muscle mechanical performance. Time courses of force production (A) and force‐generating capacity (B) were measured in vivo throughout the 6‐min fatiguing bout of exercise performed simultaneously to the dynamic 31P‐MRS acquisition. Maximal contractile force produced during the whole exercise (C), extent of force reduction measured at the exercise end (D) and total amount of force production during the whole exercise (E). For the panels A and B, P Anova indicates the overall result of the two‐way repeated measures analysis of variance, and Tukey post‐hoc multiple comparisons were used to determine pairwise time‐points differences. Data are means ± SEM. *Significantly different from Tp53inp1+/+.
Figure 6
Figure 6
Noninvasive investigation of gastrocnemius muscle bioenergetics using dynamic 31P‐MRS. Changes in (phosphocreatine [PCr]) (A), [ATP] (B), [ADP] (C) and pH (D) were measured throughout the 6‐min fatiguing bout of exercise and the 15‐min postexercise recovery period. For each panel, the first time‐point (t = 0) indicates the basal value. Data are means ± SEM.
Figure 7
Figure 7
Gastrocnemius muscle oxidative function and proton efflux. Oxidative ATP production at the end of the 6‐min fatiguing bout of exercise (A), initial rate (B) and time constant (C) of phosphocreatine (PCr) resynthesis at the start of the postexercise recovery period, maximal oxidative capacity (D) and proton efflux (E). Data are means ± SEM. *Significantly different from Tp53inp1+/+.

Similar articles

See all similar articles

References

    1. Allen D. G., Lannergren J., and Westerblad H.. 1997. The role of ATP in the regulation of intracellular Ca2+ release in single fibres of mouse skeletal muscle. J. Physiol. (Lond.) 498:587–600. - PMC - PubMed
    1. Anflous K., Armstrong D. D., and Craigen W. J.. 2001. Altered mitochondrial sensitivity for ADP and maintenance of creatine‐stimulated respiration in oxidative striated muscles from VDAC1‐deficient mice. J. Biol. Chem. 276:1954–1960. - PubMed
    1. Arnold D. L., Bore P. J., Radda G. K., Styles P., and Taylor D. J.. 1984. Excessive intracellular acidosis of skeletal muscle on exercise in a patient with a post‐viral exhaustion/fatigue syndrome. A 31P nuclear magnetic resonance study. Lancet 1:1367–1369. - PubMed
    1. Baumgartner B. G., Orpinell M., Duran J., Ribas V., Burghardt H. E., Bach D., et al. 2007. Identification of a novel modulator of thyroid hormone receptor‐mediated action. PLoS ONE 2:e1183. - PMC - PubMed
    1. Bhatti J. S., Bhatti G. K., and Reddy P. H.. 2017. Mitochondrial dysfunction and oxidative stress in metabolic disorders – a step towards mitochondria based therapeutic strategies. Biochim. Biophys. Acta 1863:1066–1077. - PMC - PubMed

Publication types

Feedback