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Review
. 2022 Feb 9:13:834597.
doi: 10.3389/fphys.2022.834597. eCollection 2022.

Ergothioneine Improves Aerobic Performance Without Any Negative Effect on Early Muscle Recovery Signaling in Response to Acute Exercise

Théo Fovet  1 , Corentin Guilhot  1 , Pierre Delobel  1 , Angèle Chopard  1 , Guillaume Py  1 , Thomas Brioche  1
Affiliations
Review

Ergothioneine Improves Aerobic Performance Without Any Negative Effect on Early Muscle Recovery Signaling in Response to Acute Exercise

Théo Fovet et al. Front Physiol. .

Abstract

Physical activity is now recognized as an essential element of healthy lifestyles. However, intensive and repeated exercise practice produces a high level of stress that must be managed, particularly oxidative damage and inflammation. Many studies investigated the effect of antioxidants, but reported only few positive effects, or even muscle recovery impairment. Secondary antioxidants are frequently highlighted as a way to optimize these interactions. Ergothioneine is a potential nutritional supplement and a secondary antioxidant that activates the cellular NRF2 pathway, leading to antioxidant response gene activation. Here, we hypothesized that ergothioneine could improve performance during aerobic exercise up to exhaustion and reduce exercise-related stress without impairing early muscle recovery signaling. To test this hypothesis, 5-month-old C56B6J female mice were divided in two groups matched for maximal aerobic speed (MAS): control group (Ctrl; n = 9) and group supplemented with 70 mg ergothioneine/kg/day (ET; n = 9). After 1 week of supplementation (or not), mice performed a maximum time-to-exhaustion test by running on a treadmill at 70% of their MAS, and gastrocnemius and soleus muscles were collected 2 h after exercise. Time to exhaustion was longer in the ET than Ctrl group (+41.22%, p < 0.01). Two hours after exercise, the ET group showed higher activation of protein synthesis and satellite cells, despite their longer effort. Conversely, expression in muscles of metabolic stress and inflammation markers was decreased, as well as oxidative damage markers in the ET group. Moreover, ergothioneine did not seem to impair mitochondrial recovery. These results suggest an important effect of ergothioneine on time-to-exhaustion performance and improved muscle recovery after exercise.

Keywords: antioxidant; ergothioneine; exercise; exercise performance; exercise recovery; muscle.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Experimental protocol. Mice were acclimatized to their cages for 2 weeks, before undergoing four treadmill running habituation sessions. One week before supplementation initiation, the maximal aerobic speed (MAS) was measured by running on the treadmill. Then, mice were distributed in the control (Ctrl) and ergothioneine (ET) supplementation group according to their MAS. After 1 week of ET supplementation (or not for the Ctrl group), mice performed a time to exhaustion test at 70% of their individual MAS. Puromycin was injected 100 min after the test end and muscles were collected after sacrifice at 120 min after the exercise end.
Figure 2
Figure 2
Functional tests. (A) Maximal aerobic speed (treadmill running; m/min) in the ergothioneine (ET; n = 9) and control (Ctrl; n = 9) groups before starting ergothioneine supplementation. (B) Time to exhaustion test (min) by running on a treadmill at 70% of the maximal aerobic speed after 1 week of ergothioneine supplementation (ET) or not (Ctrl). *p < 0.05, **p < 0.01 vs. Ctrl.
Figure 3
Figure 3
Ergothioneine effect on protein synthesis markers at 2 h post-exercise. Evaluation of puromycin incorporation and protein synthesis marker expression in soleus (n = 2/mouse) and gastrocnemius (n = 1/mouse) samples. (A) Quantification of protein synthesis by measuring puromycin incorporation in muscles. (B) Phosphorylated 4EBP1 (Ser65)/total 4EBP1 protein ratio post-exercise. (C) Phosphorylated RPS6 (Ser240/244)/total RPS6 protein ratio. (D) Representative Western Blots. *p < 0.05; ** p < 0.01 vs. Ctrl.
Figure 4
Figure 4
Ergothioneine effect on transcription of protein synthesis markers. Expression of genes encoding protein synthesis markers in gastrocnemius samples (n = 1/mouse). (A) IGF1 mRNA level. (B) Akt mRNA level. (C) Mtor mRNA level. (D) 4ebp1 mRNA level. (E) Rps6 mRNA level; *p < 0.05 vs. Ctrl.
Figure 5
Figure 5
Ergothioneine effect on ubiquitin proteasome markers (UPS) 2 h after exercise. UPS markers in soleus and gastrocnemius samples and expression of genes encoding UPS markers in gastrocnemius samples. (A) Total ubiquitinated proteins. (B) MAFbx protein expression. (C) MurF1 protein expression. (D) Mafbx mRNA expression. (E) MurF1 mRNA expression. (F) Representative Western Blots; *p < 0.05 vs. Ctrl.
Figure 6
Figure 6
Ergothioneine effect on autophagy markers 2 h after exercise. Autophagy markers in soleus and gastrocnemius muscle and expression of genes encoding autophagy markers in gastrocnemius muscle. (A) Phosphorylated ULK1 (Ser757)/total ULK1 ratio. (B) LC3.2/LC3.1 protein ratio. (C) p62 protein expression. (D) Atg7 mRNA level. (E) Pink1 mRNA level. (F) Parkin mRNA level. (G) Representative Western Blots; **p < 0.01 vs. Ctrl.
Figure 7
Figure 7
Ergothioneine effect on metabolic stress markers 2 h after exercise. Metabolic stress markers in soleus and gastrocnemius muscle and expression of genes encoding metabolic markers in gastrocnemius muscle. (A) Phosphorylated AMPKa (Thr172)/total AMPKa ratio. (B) Redd1 protein expression. (C) Phosphorylated GSK3 (Ser21/9)/total GSK3 ratio. (D) AMPKa mRNA level. (E) Redd1 mRNA level. (F) Gsk3 mRNA level. (G) Representative Western Blots; *p < 0.05; **p <0.01 vs. Ctrl.
Figure 8
Figure 8
Ergothioneine effect on muscle inflammatory markers 2 h after exercise. Inflammatory marker (protein and gene) expression in soleus and gastrocnemius samples. (A) TNF-a protein expression. (B) IL-1b protein expression. (C) Tnfa mRNA level. (D) IL-1b mRNA level. (E) IL6 mRNA level. (F) Representative Western Blots; *p < 0.05 vs. Ctrl.
Figure 9
Figure 9
Ergothioneine effect on oxidative stress markers 2 h after exercise. Oxidative stress markers in soleus and gastrocnemius samples. (A) 4HNE adduct quantification. (B) Oxidized protein expression. (C) Phosphorylated p53 (Ser15)/total p53 ratio. (D) Phosphorylated p38(Thr180/Tyr182)/p38 ratio. (E) Representative Western Blots; *p < 0.05 vs. Ctrl.
Figure 10
Figure 10
Ergothioneine effect on antioxidant defense markers 2 h after exercise. Antioxidant defense markers in soleus and gastrocnemius samples. (A) SOD1 protein expression. (B) SOD2 protein expression. (C) SOD1 mRNA level. (D) SOD2 mRNA level. (E) Gpx1 mRNA level. (F) Nrf2 mRNA level. (G) Representative Western Blots; *p < 0.05 vs. Ctrl.
Figure 11
Figure 11
Ergothioneine effect on mitochondrial markers 2 h after exercise. Mitochondrial markers. (A) Cytochrome C protein expression. (B) COX IV protein expression. (C) PGC1a protein expression. (D) PGC1a mRNA level. (E) NRF1 mRNA level. (F) Tfam mRNA level. (G) Representative Western Blots; *p < 0.05 vs. Ctrl.
Figure 12
Figure 12
Ergothioneine effect on satellite cell markers 2 h after exercise. Satellite cell markers in soleus and gastrocnemius samples. (A) PAX7 protein expression. (B) MyoD protein expression. (C) Myf-5 protein expression. (D) Myogenin protein expression. (E) Spry-1 protein expression. (F) Representative Western Blots; *p < 0.05; **p < 0.01 vs. Ctrl.
Figure 13
Figure 13
Ergothioneine effect on transcription regulation of satellite cell markers. Satellite cell marker transcription regulation in gastrocnemius muscle. (A) Pax7 mRNA level. (B) MyoD mRNA level. (C) Myogenin mRNA level. *p < 0.05 vs. Ctrl.
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