Long-term iron supplementation combined with vitamin B6 enhances maximal oxygen uptake and promotes skeletal muscle-specific mitochondrial biogenesis in rats

Lei Zhou; Soroosh Mozaffaritabar; Attila Kolonics; Takuji Kawamura; Atsuko Koike; Johanna Kéringer; Yaodong Gu; Roman Karabanov; Zsolt Radák

doi:10.3389/fnut.2023.1335187

Long-term iron supplementation combined with vitamin B6 enhances maximal oxygen uptake and promotes skeletal muscle-specific mitochondrial biogenesis in rats

Front Nutr. 2024 Jan 15:10:1335187. doi: 10.3389/fnut.2023.1335187. eCollection 2023.

Authors

Lei Zhou^#¹, Soroosh Mozaffaritabar^#¹, Attila Kolonics¹, Takuji Kawamura^{1

2}, Atsuko Koike³, Johanna Kéringer¹, Yaodong Gu⁴, Roman Karabanov⁵, Zsolt Radák^{1

2}

Affiliations

¹ Research Institute of Molecular Exercise Science, Hungarian University of Sport Science, Budapest, Hungary.
² Waseda Institute for Sport Sciences, Waseda University, Saitama, Japan.
³ Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, Japan.
⁴ Faculty of Sports Science, Ningbo University, Ningbo, China.
⁵ Synthesit Swiss SA, Genève, Switzerland.

^# Contributed equally.

Abstract

Introduction: Iron is an essential micronutrient that plays a crucial role in various biological processes. Previous studies have shown that iron supplementation is related to exercise performance and endurance capacity improvements. However, the underlying mechanisms responsible for these effects are not well understood. Recent studies have suggested the beneficial impact of iron supplementation on mitochondrial function and its ability to rescue mitochondrial function under adverse stress in vitro and rodents. Based on current knowledge, our study aimed to investigate whether the changes in exercise performance resulting from iron supplementation are associated with its effect on mitochondrial function.

Methods: In this study, we orally administered an iron-based supplement to rats for 30 consecutive days at a dosage of 0.66 mg iron/kg body weight and vitamin B6 at a dosage of 0.46 mg/kg.

Results: Our findings reveal that long-term iron supplementation, in combination with vitamin B6, led to less body weight gained and increased VO₂ max in rats. Besides, the treatment substantially increased Complex I- and Complex II-driven ATP production in intact mitochondria isolated from gastrocnemius and cerebellum. However, the treatment did not change basal and succinate-induced ROS production in mitochondria from the cerebellum and skeletal muscle. Furthermore, the iron intervention significantly upregulated several skeletal muscle mitochondrial biogenesis and metabolism-related biomarkers, including PGC-1α, SIRT1, NRF-2, SDHA, HSL, MTOR, and LON-P. However, it did not affect the muscular protein expression of SIRT3, FNDC5, LDH, FIS1, MFN1, eNOS, and nNOS. Interestingly, the iron intervention did not exert similar effects on the hippocampus of rats.

Discussion: In conclusion, our study demonstrates that long-term iron supplementation, in combination with vitamin B6, increases VO₂ max, possibly through its positive role in regulating skeletal muscle-specific mitochondrial biogenesis and energy production in rats.

Keywords: VO2 max; exercise performance; iron supplementation; mitochondrial biogenesis; skeletal muscle; vitamin B6.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. ZR receives support from the National Excellence Program (126823) and the Scientific Excellence Program, TKP2020-NKA-17 and TKP2021-EGA-37, at the Hungarian University of Sport Science, Innovation and Technology Ministry, Hungary.