Tomatidine, A steroidal compound protects against muscle atrophy

Published: admin | Format: 2017-02-27

What is tomatidine?

Tomatidine is a steroidal alkaloid and the aglycone of α- tomatine, an abundant glycoalkaloid in tomato plants that mediates plant defense against fungi, bacteria, viruses, and predatory insects. When consumed by animals, α- tomatine is hydrolyzed by stomach acid and intestinal bacteria to tomatidine, which is absorbed by the gut[1] and performs as a bioactive compound in vivo.


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Functions

Ø  Stimulates skeletal muscle hypertrophy

Tomatidine could stimulates skeletal muscle hypertrophy and reduces skeletal muscle atrophy by activating(but not sustained increase) mTORC1 signaling and inhibiting atrophy mediators ATF4[2]. via several mechanisms including increased protein synthesis, increased mitochondrial biogenesis, and increased expression of anabolic genes encoding insulin-like growth factor-1 (IGF-1) and peroxisome proliferator-activated receptor-γ coactivator-1α1 (PGC-1α1).

 

Young mice (7 weeks old) supplemented with 0.05% (w/w) tomatidine for five weeks, tomatidine increased mTORC1 activity, as evidenced by increased S6K phosphorylation (Fig. 1A), increased total cellular protein (Fig. 1B), increased mitochondrial DNA (Fig. 1C), increased IGF1 and PGC-1α1 mRNAs (Fig. 1D), and increased PGC-1α1 pro-tein (Fig. 1E).

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Fig. 1 Tomatidine stimulates skeletal muscle hypertrophy

 

Ø  Reduced Fat Mass

Tomatidine increased skeletal muscle, it did not increase total body weight, suggesting that tomatidine reduced the weight of another tissue (Fig. 2A). Tomatidine increased lean mass, but reduced fat mass (Fig. 2B). Further-more, tomatidine significantly reduced the weights of the epididymal, retroperitoneal and scapular fat pads (Fig. 2C), which was explained by a reduction in adipocyte size (Fig. 2D, E and F).

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                   Fig. 2 Tomatidine reduced adiposity

 

Ø  Improves muscle function: strength and exercise capacity

Tomatidine significantly increased skeletal muscle fiber size, and the overall increase in skeletal muscle mass was 13.7± 0.0% (p <0.001). Grip strength in vivo (Fig. 3A) and specific muscle force ex vivo (Fig. 3B) were also significantly increased. Furthermore, running distance on an accelerating treadmill (Fig. 3C) was increased.

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Fig 3. Tomatidine improves muscle function

 

Other functions:

Ø  Cardiovascular protection: Daily intake of tomatidine supplementation may also reduce the risk of cardiovascular diseases. Fujiwara et al. found that dietary tomatidine significantly ameliorated hyperlipidemia (inhibit cholesterol ester accumulation in human monocyte-derived macrophages and reduced the serum cholesterol levels) and atherosclerosis in apoE-deficient mice by inhibiting acyl-A: cholesterol acyl-transferase(ACAT) activity[3].

Ø  Anticarcinogenic effect: Lavie et al. reported that tomatidine acted as a potent and effective chemosensitizer in multidrug-resistant tumor cells, sensitizing the cells to the cytotoxic action of adriamycin and verapamil[4]. Tomatidine does not effectively inhibit the viability of the A540 cells and nontoxic doses of tomatidine suppressed cell invasion, did not affect cell migration, reduced mRNA levels of MMP-2 and MMP-9, increased the expression of tissue inhibitor metalloproteinase-1 (TIMP-1), and inhibited NF-κB activity and ERK and Akt signaling pathways[5].

Ø  Anti-inflammatory effect: Chiu investigated anti-inflammatory effects of tomatidine and in LPS-stimulated macrophages. Tomatidine decreased inducible nitric oxide synthase and cyclooxygenase-2 expression through suppression of I-kBα phosphorylation, NF-κB nuclear translocation, and JNK activation[6].

Ø  Antibacterial activity: Mitchell et al. investigated the inhibition by tomatidine of Staphylococcus aureus small-colony variants (SCVs) in cystic fibrosis airway epithelial cells. SCVs are often associated with S. aureus infection encountered by cystic fibrosis patients. Tomatidine was a potent growth inhibitor of SCVs at a minimum inhibitory concentration (MIC) of 0.12 μg/mL [7].

 

Safety & Recommended Dose

As a natural ingredient, tomatidine would be considered safe. The following LD50 values have

been reported for tomatine in mice (in mg/kg body weight): ip, 25−33.5; iv, 18; oral, 500; subcutaneous, >1000[8,9]. Tomsik et al.[10] note that the 1 mg/kg dose of tomatine they used in their mouse study is a safe dose, which would most likely be similar with tomatidine. Koh, et al. found that no unwarranted side effects when studying humans who consumed “indigenous variants of tomatoes with very high concentrations of α-tomatine (up to 0.05% (w/w) of dry tomato weight)”[11].

 

Tomatidine results in a much less toxic molecule in both pregnant and non-pregnant mice as compared to the structurally similar solasodine[12]. Gaffield and Keeler reported the following relative oral teratogenicities in hamsters: jervine, 100; a-chaconine,43; a-solanine, 32; solanidine, 32; a-tomatine, 1; tomatidine,0[13].

 

Current supplements offer a dose of between 10-50mg per serve. It is said that for optimal absorption, splitting the dose to 1-4 servings/day may be ideal.

 

References:

[1] Dyle MC, Ebert SM, Cook DP, et al. Systems-based Discovery of Tomatidine as a Natural Small Molecule Inhibitor of Skeletal Muscle Atrophy. The Journal of Biological Chemistry. 2014, 289(21):14913-14924.

[2] Ebert SM, Dyle MC, Bullard SA, et al. Identification and Small Molecule Inhibition of an Activating Transcription Factor 4 (ATF4)-dependent Pathway to Age-related Skeletal Muscle Weakness and Atrophy. The Journal of Biological Chemistry. 2015,290(42):25497-25511.

[3] Fujiwara, Y. et al. Tomatidine, a tomato sapogenol, ameliorates hyperlipidemia and atherosclerosis in ApoE-deficient mice by inhibiting acyl-CoA:cholesterol acyl-transferase (ACAT). J. Agric. Food Chem. 2012, 60, 2472−2479.

[4] Lavie, Y. et al. Inhibitory effect of steroidal alkaloids on drug transport and multidrug resistance in human cancer cells. Anticancer Res. 2001, 21, 1189−1194.

[5] Yan, K.-H. et al. Tomatidine inhibits invasion of human lung adenocarcinoma cell A549 by reducing matrix metalloproteinases expression. Chem.Biol. Interact. 2013, 203, 580−587.

[6] Chiu, F. L.; Lin, J. K. Tomatidine inhibits iNOS and COX-2 through suppression of NF-κB and JNK pathways in LPS-stimulated mouse macrophages. FEBS Lett. 2008, 582, 2407−2412.

[7] Mitchell, G. et al. Tomatidine inhibits replication of Staphylococcus aureus small-colony variants in cystic fibrosis airway epithelial cells. Antimicrob. Agents Chemother. 2011, 55, 1937−1945.

[8] Sackmann, W.; Kern, H., Wiesmann, E.; Studies on the biological effects of solanine and tomatine.; Schweiz. Z. Allg. Pathol. Bakteriol., 1959; 22, 557-563.

[9] Mendel Friedman. Anticarcinogenic, Cardioprotective, and Other Health Benefits of Tomato Compounds Lycopene, αTomatine, and Tomatidine in Pure Form and in Fresh and Processed Tomatoes, J. Agric. Food Chem. 2013, 61, 9534−9550

[10]Tomsik, P. et al. The anticancer activity of alpha-tomatine against mammary adenocarcinoma in mice. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech. Repub. 2013, 157, 153−161.

[11] Koh, E., Kaffka, S. and Mitchell, A. E. (2013), A long-term comparison of the influence of organic and conventional crop management practices on the content of the glycoalkaloid α-tomatine in tomatoes. J. Sci. Food Agric., 93: 1537–1542.

[12] Friedman, M. et al. Effect of feeding solanidine, solasodine and tomatidine to non-pregnant and pregnant mice. Food Chem. Toxicol. 2003, 41, 61−71.

[13] Gaffield, W. et al. Induction of terata in hamsters by solanidine alkaloids derived from Solanum tuberosum. Chemical Research in Toxicology,1996, 9, 426–433.



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