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. 2022 Sep 21;14(19):3904.
doi: 10.3390/nu14193904.

Limonium tetragonum Promotes Running Endurance in Mice through Mitochondrial Biogenesis and Oxidative Fiber Formation

Yong Gyun Lee  1 , Mi-Young Song  2 , Hwangeui Cho  1 , Jong Sik Jin  3 , Byung-Hyun Park  2 , Eun Ju Bae  1
Affiliations

Limonium tetragonum Promotes Running Endurance in Mice through Mitochondrial Biogenesis and Oxidative Fiber Formation

Yong Gyun Lee et al. Nutrients. .

Abstract

The purpose of this study was to examine whether Limonium tetragonum, cultivated in a smart-farming system with LED lamps, could increase exercise capacity in mice. C57BL/6 male mice were orally administered vehicle or Limonium tetragonum water extract (LTE), either 30 or 100 mg/kg, and were subjected to moderate intensity treadmill exercise for 4 weeks. Running distance markedly increased in the LTE group (100 mg/kg) by 80 ± 4% compared to the vehicle group, which was accompanied by a higher proportion of oxidative fibers (6 ± 6% vs. 10 ± 4%). Mitochondrial DNA content and gene expressions related to mitochondrial biogenesis were significantly increased in LTE-supplemented gastrocnemius muscles. At the molecular level, the expression of PGC-1α, a master regulator of fast-to-slow fiber-type transition, was increased downstream of the PKA/CREB signaling pathway. LTE induction of the PKA/CREB signaling pathway was also observed in C2C12 cells, which was effectively suppressed by PKA inhibitors H89 and Rp-cAMP. Altogether, these findings indicate that LTE treatment enhanced endurance exercise capacity via an improvement in mitochondrial biosynthesis and the increases in the formation of oxidative slow-twitch fibers. Future study is warranted to validate the exercise-enhancing effect of LTE in the human.

Keywords: Limonium tetragonum water extract; endurance exercise; exercise mimetic; mitochondrial biogenesis; slow myofiber formation; smart-farming system.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Analysis of Limonium tetragonum water extract (LTE). (A) LC/Q-TOF MS chromatogram (intensity measured in counts per second, cps) of LTE using negative ion mode. (B) Structures of the predominant substances in LTE. (1): epicatechin (2): (−)-epigallocatechin-3-gallate, (3): myricetin-3-O-β-D-galactopyranoside, (4): myricetin-3-O-α-L-rhamnopyranoside, (5): myricetin-3-O-(2″-O-galloyl)-α-L-rhamnopyranoside, and (6): myricetin-3-O-(3″-O-galloyl)-α-L-rhamnopyranoside.
Figure 2
Figure 2
Effects of LTE supplementation on treadmill running endurance. (A) Schematic of experimental design to assess the effect of LTE on exercise performance. (B,C) Body weight change after the 4-week exercise and LTE supplementation program, and daily food intake of mice (n = 8). (D) Running population plotted against time to exhaustion (10 min at 10 m/min with an increase in running speed by 2 m/min every 10 min to a maximum of 16 m/min). Total running time until exhaustion was determined (n = 8). (E,F) Average running time and running distance until exhaustion under a forced running exercise-to-exhaustion test using data acquired during the last two weeks of testing (n = 8). Values are mean ± S.E.M., * p < 0.05 and ** p < 0.01. LTE-30, LTE 30 mg/kg p.o.; LTE-100, LTE 100 mg/kg p.o.
Figure 3
Figure 3
Effects of LTE supplementation on the proportion of muscle fiber-types. (A) Representative microscopic images of GAS muscles immunostained with anti-MyHC antibodies (types I, IIa, IIb, and IIx). The number of the different types of muscle fibers was counted manually (n = 5). Results are graphed as a percentage of the total number of fibers per muscle. (B) The quantification of the cross-sectional area of each type of myofibers in GAS muscles of mice is described in (A). (C) The cross-sectional area of each type of muscle fiber was determined based on the expression of MyHC-positive myofibers. (D) Succinate dehydrogenase (SDH) activity staining was performed on sections of GAS muscle (n = 3). (E) mRNA levels of known markers of type I and type II fibers were analyzed by qPCR. mRNA levels were standardized against Gapdh and plotted relative to the expression in vehicle-treated mice (n = 7–8). Values are mean ± S.E.M., * p < 0.05 and ** p < 0.01. LTE-100, LTE 100 mg/kg p.o.
Figure 4
Figure 4
Effects of LTE supplementation on mitochondrial biogenesis. (A) Mitochondrial DNA (mtDNA) was quantified by qPCR using nuclear DNA (nDNA) as a standard (n = 3–5). (B) qPCR analysis of genes related to mitochondrial biogenesis in GAS muscles (n = 6–8). The expression of each gene was normalized with housekeeping gene Gapdh, whereas the expression of mitochondrial genome-encoded genes Mtco1 and Mtco2 was normalized with Ppia. (C) Western blotting analysis of the expression of OxPhos subunits and quantification of the intensity of OxPhos subunits relative to vehicle. (D) Western blotting analysis of mitochondrial fission and fusion genes. Western blot values are mean ± S.E.M (n = 3–6). * p < 0.05 and ** p < 0.01. LTE-100, LTE 100 mg/kg p.o.
Figure 5
Figure 5
Effects of LTE supplementation on the signaling pathways leading to mitochondrial biogenesis and function. (A) Western blotting analysis of the genes involved in mitochondrial biogenesis in GAS muscles. Quantification results are shown (n = 4–6). (B) qPCR analysis of genes related to mitochondrial biogenesis (n = 4–9). Expression of each gene was normalized with housekeeping gene Gapdh. (C) Western blotting of PKA substrates. The red Ponceau S-stained gel is shown as loading control. Values are mean ± S.E.M. * p < 0.05 and ** p < 0.01. LTE-100, LTE 100 mg/kg p.o.
Figure 6
Figure 6
Effects of LTE treatment of C2C12 cells. C2C12 cells were incubated with LTE 30 μg/mL for 5 days in the differentiation medium. (A) Western blotting analysis of MyHC isoforms. Quantification results are shown (n = 4–6). (B) Western blotting for OxPhos proteins (n = 6). (C) qPCR analysis of the expression of Ppargc1a (encoding PGC-1α) and Nfatc1 (n = 4). (D) Western blotting analysis after co-treatment of H89 (10 μM) and LTE. LTE, LTE 30 μg/mL; MyHC, myosin heavy chain; PGC-1α, peroxisome proliferator-activated receptor γ coactivator 1α; Nfatc1, nuclear factor of activated T cell 1. Values are mean ± S.E.M. * p < 0.05 and ** p < 0.01.
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This paper was supported by a grant from the Medical Research Center Program (2017R1A5A2015061) and by a grant from the Basic Science Research Program (2020R1A2C2004761) through the Nation Research Foundation (NRF), which was funded by the Korean government (MSIP). This paper was also supported by a grant from the Technology Innovation Program (20012892) funded by the Ministry of Trade, Industry & Energy (MOTIE, Korea).

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