Place · Level 3 · Supplement
Trimethylglycine / Betaine
甘氨酸戴 3 个甲基 · 同型半胱氨酸再甲基化双轨制副路 · MTHFR 突变者最受益 · 一碳代谢最后一块拼图
Last updated
Story path
Chapter 1
Glycine with 3 methyls
Glycine with 3 methyls
TMG (trimethylglycine) = glycine + three methyl groups (-N(CH₃)₃⁺); its formal chemical name is betaine — named because it was first isolated from sugar beet (*Beta vulgaris*) in 1866.
Chemical structure:
The amine group (-NH₂) of glycine is replaced by three methyls → a quaternary ammonium compoundPositive and negative charges coexist (-N(CH₃)₃⁺ + -COO⁻) → a zwitterion, which is the root of its 'osmolyte' (osmoprotectant) propertyWater-soluble, mildly sweet (this is also where the '-ine' suffix in 'betaine' comes from)
Two independent roles:
1. Cellular osmoprotectant: protects cellular protein structure under hypertonic (high-salt) or dehydrated conditions (a member of the same osmolyte family as taurine / sorbitol / creatine)
2. Methyl donor: via the BHMT enzyme, it donates a methyl group to homocysteine → methionine (next scene)
Two ways the body obtains TMG:
Food: wheat germ / whole wheat / spinach / beetroot / quinoa / seafood (scallops, shrimp)Endogenous synthesis: choline → betaine — choline dehydrogenase + BADH in mitochondria oxidize choline in two steps into TMG
The second path links TMG directly to the choline story — choline is not just raw material for phospholipids / ACh / hepatic lipid transport, it is also the endogenous precursor of TMG and therefore supports the dual-track methylation system.
Chemical structure:
The amine group (-NH₂) of glycine is replaced by three methyls → a quaternary ammonium compoundPositive and negative charges coexist (-N(CH₃)₃⁺ + -COO⁻) → a zwitterion, which is the root of its 'osmolyte' (osmoprotectant) propertyWater-soluble, mildly sweet (this is also where the '-ine' suffix in 'betaine' comes from)
Two independent roles:
1. Cellular osmoprotectant: protects cellular protein structure under hypertonic (high-salt) or dehydrated conditions (a member of the same osmolyte family as taurine / sorbitol / creatine)
2. Methyl donor: via the BHMT enzyme, it donates a methyl group to homocysteine → methionine (next scene)
Two ways the body obtains TMG:
Food: wheat germ / whole wheat / spinach / beetroot / quinoa / seafood (scallops, shrimp)Endogenous synthesis: choline → betaine — choline dehydrogenase + BADH in mitochondria oxidize choline in two steps into TMG
The second path links TMG directly to the choline story — choline is not just raw material for phospholipids / ACh / hepatic lipid transport, it is also the endogenous precursor of TMG and therefore supports the dual-track methylation system.
Dietary TMG intake
Food TMG content (mg / 100 g):Wheat bran / wheat germ: 1300-1500 mg — far aheadSpinach: 600-650 mgBeetroot: 130-260 mg (raw vs cooked)Quinoa: ~400 mgShrimp / scallops: 200-300 mgWhole wheat bread: 200 mgWhite rice / refined pasta: ~10-20 mg (90% lost in milling)
Typical intake:
US NHANES: median ~200-300 mg/day (heavy whole-grain eaters 600-1000 mg/day; refined diets <100 mg/day)AI / RDA: no official RDA — TMG is not an essential nutrient (because endogenous choline can synthesize it), but when long-term low intake + low choline + low B12/folate coincide, both methylation tracks are impaired at once
Relationship to choline:
1 g choline → two-step mitochondrial oxidation → ~0.7 g TMGSo eating more eggs + offal + fish: supplements choline + directly raises the TMG poolVery low choline + very low TMG (vegan + refined grains) → both upstream substrates for the methylation backup (BHMT) drop together
Practical:
There is no deficiency syndrome — the body can synthesize from choline → so food not hitting 'ideal' doesn't immediately cause problemsIf you eat whole grains + spinach + eggs: almost certainly enoughIf you eat refined rice / white flour / no leafy greens or eggs: adding 5-15 g wheat germ to yogurt / salad is 10× more cost-effective than a supplement
化学 · 名字与结构从哪来
TMG (trimethylglycine, 三甲基甘氨酸) = 甘氨酸 + 三个甲基 (-N(CH₃)₃⁺), 化学正式名称 甜菜碱 (betaine) —— 因为 1866 年首次从甜菜根 (Beta vulgaris) 分离出来而得名。化学结构:
甘氨酸的氨基 (-NH₂) 被三个甲基取代 → 季铵化合物 (quaternary ammonium)正负电荷共存 (-N(CH₃)₃⁺ + -COO⁻) → 两性离子, 这是它渗透压调节子 (osmolyte) 性质的根源水溶性, 微甜 (这也是 betaine 命名后缀 -ine 的来源)
两个独立角色:
1. 细胞渗透压调节子: 在高渗 (高盐) 或脱水状态下保护细胞蛋白结构 (与 taurine / sorbitol / 肌酸一样的 osmolyte 家族)
2. 甲基供体: 通过 BHMT 酶 提供一个甲基给同型半胱氨酸 → 蛋氨酸 (下一幕讲)
内源合成那一步: 线粒体里的胆碱脱氢酶 + BADH 把胆碱两步氧化为 TMG。所以胆碱不只是磷脂 / ACh / 肝脂质运输的原料, 还是 TMG 的内源前体, 进而支撑甲基化双轨制。
Chapter 2
BHMT alternate route
BHMT alternate route
TMG's most important role in the atlas: the backup pathway for homocysteine remethylation.
Recap of the main pathway (covered in detail in the vitamin-b12/methylation L4 scene):
Homocysteine (Hcy) accumulation → cardiovascular + neurological riskMain route: MTR (methionine synthase) + methylcobalamin (B12) + 5-MTHF (folate) → Hcy + methyl → methionine (Met) → S-adenosylmethionine: The body's main methyl-group donor — it tags DNA, neurotransmitters, and more with methyl groups., the universal methyl donor → DNA / nerve myelin / neurotransmitter methylation across the boardB12 deficiency / folate deficiency / MTHFR mutation → main-route efficiency drops → Hcy rises
TMG's backup route:
BHMT enzyme (betaine-homocysteine methyltransferase)Reaction: Hcy + betaine (TMG) → methionine (Met) + dimethylglycine (DMG)Mainly expressed in liver and kidney (almost not at all in other tissues)Does not require B12 / folate — completely independent of the main route
Evolutionary meaning of the dual-track system:
The main route covers all tissues, but needs adequate B12 + folateThe backup is only in liver/kidney, but responds directly to substrate (TMG) and doesn't depend on B12/folateEvolution kept the dual-track design because the liver is the body's biggest methylation consumer (phosphatidylcholine synthesis + creatine synthesis + bile acids + detox) and needs redundancy
MTHFR C677T carriers:
How common TT homozygosity is varies sharply by ancestry (NIH ODS: ~25% of Hispanics, ~10% of Caucasians and Asians, ~1% of African Americans)MTHFR enzyme activity falls → insufficient 5-MTHF → main route (MTR) less efficient → high HcyThe backup route (BHMT + TMG) is relatively more important in these people — TMG supplementation gives larger Hcy improvement in MTHFR carriers (Olthof 2005 review)
Click 'Look more closely at this scene →' for the 4-step animation — the Hcy pool, full main vs backup contrast, and how the backup becomes the main player when MTHFR is mutated.
Core insight: TMG is not a 'magical new molecule', it is a backup power supply the body already has — supplementing it just adds substrate to a route that already exists.
Recap of the main pathway (covered in detail in the vitamin-b12/methylation L4 scene):
Homocysteine (Hcy) accumulation → cardiovascular + neurological riskMain route: MTR (methionine synthase) + methylcobalamin (B12) + 5-MTHF (folate) → Hcy + methyl → methionine (Met) → S-adenosylmethionine: The body's main methyl-group donor — it tags DNA, neurotransmitters, and more with methyl groups., the universal methyl donor → DNA / nerve myelin / neurotransmitter methylation across the boardB12 deficiency / folate deficiency / MTHFR mutation → main-route efficiency drops → Hcy rises
TMG's backup route:
BHMT enzyme (betaine-homocysteine methyltransferase)Reaction: Hcy + betaine (TMG) → methionine (Met) + dimethylglycine (DMG)Mainly expressed in liver and kidney (almost not at all in other tissues)Does not require B12 / folate — completely independent of the main route
Evolutionary meaning of the dual-track system:
The main route covers all tissues, but needs adequate B12 + folateThe backup is only in liver/kidney, but responds directly to substrate (TMG) and doesn't depend on B12/folateEvolution kept the dual-track design because the liver is the body's biggest methylation consumer (phosphatidylcholine synthesis + creatine synthesis + bile acids + detox) and needs redundancy
MTHFR C677T carriers:
How common TT homozygosity is varies sharply by ancestry (NIH ODS: ~25% of Hispanics, ~10% of Caucasians and Asians, ~1% of African Americans)MTHFR enzyme activity falls → insufficient 5-MTHF → main route (MTR) less efficient → high HcyThe backup route (BHMT + TMG) is relatively more important in these people — TMG supplementation gives larger Hcy improvement in MTHFR carriers (Olthof 2005 review)
Click 'Look more closely at this scene →' for the 4-step animation — the Hcy pool, full main vs backup contrast, and how the backup becomes the main player when MTHFR is mutated.
Core insight: TMG is not a 'magical new molecule', it is a backup power supply the body already has — supplementing it just adds substrate to a route that already exists.
Why BHMT is liver/kidney only
BHMT expression is restricted to liver and kidney — this is not random distribution, it aligns with the organs that consume the most methyl groups.Liver methylation consumption:
PEMT pathway: phosphatidylethanolamine → phosphatidylcholine (PC); each reaction consumes 3 S-adenosylmethionine: The body's main methyl-group donor — it tags DNA, neurotransmitters, and more with methyl groups. methyl groupsCreatine synthesis: GAA + SAM → creatine + SAH, accounts for 40-70% of the body's SAM usage, mostly in the liverBile acid conjugation / detoxification: large amount of small-molecule methylationDNA methylation: throughout the body, but denser in the liver as the metabolic hub
Kidney's special role:
High concentrations of osmolytes (including TMG) for medullary urine concentrationThe final step of creatine synthesis (GAA → creatine methylation) is partly in the kidneyIn chronic kidney disease, BHMT activity drops → indirectly raises Hcy → cardiovascular risk rises
Why other tissues don't express BHMT:
Brain / nerve / muscle / red cells rely on the MTR main routeNerve myelin maintenance + neurotransmitter methylation (covered in vitamin-b12/methylation) must have adequate B12 + folateThis is why vegan B12 deficiency causes neurological damage, but supplementing TMG cannot rescue nerve tissue — BHMT is not expressed there; in neural tissue TMG can only act as an osmolyte, not remethylate Hcy
So TMG's clinical positioning:
Can solve: systemic plasma Hcy reduction + liver methylation burden + some metabolic syndrome markersCannot solve: nerve-tissue B12 deficiency in vegans / strict vegetarians
This section is another concrete instance of the atlas's 'mechanism location determines clinical applicability' teaching — a molecule being effective is not enough, you also have to ask where it is effective.
nih-ods-folate
术语 · 主路与副路的分子名
回顾主路 (在 vitamin-b12/methylation L4 那一幕详细讲过):同型半胱氨酸 (Hcy) 累积 → 心血管 + 神经病变风险主路: MTR (蛋氨酸合酶) + 甲钴胺 (B12) + 5-MTHF (folate) → Hcy + 甲基 → 蛋氨酸 (Met) → S-adenosylmethionine: The body's main methyl-group donor — it tags DNA, neurotransmitters, and more with methyl groups. 通用甲基供体 → DNA / 神经髓鞘、神经递质甲基化全套缺 B12 / 缺 folate / MTHFR 突变 → 主路效率下降 → Hcy 升高
TMG 的副路:
BHMT 酶 (甜菜碱-同型半胱氨酸甲基转移酶, betaine-homocysteine methyltransferase)反应: Hcy + 甜菜碱 (TMG) → 蛋氨酸 (Met) + 二甲基甘氨酸 (DMG)主要在肝脏 + 肾脏表达 (其它组织几乎没有)不需要 B12 / folate —— 完全独立于主路
双轨制的演化意义:
主路覆盖所有组织, 但需要 B12 + folate 充足副路只在肝肾, 但对原料 (TMG) 直接响应, 不依赖 B12/folate演化保留双轨制是因为肝脏是身体最大的甲基化耗户 (磷脂酰胆碱合成 + 肌酸合成 + 胆汁酸 + 解毒)——需要冗余
MTHFR C677T 携带者有多常见: TT 纯合的比例随族群差别很大 (NIH ODS: 西语裔约 25%, 白人与亚洲人各约 10%, 非裔美国人约 1%)。
核心洞察: TMG 不是神奇的新分子, 是身体本来就有的备用电源——补它只是给已经存在的副路加底料。
Chapter 3
Hcy clinical RCT
Hcy clinical RCT
The clinical evidence that TMG lowers homocysteine (Hcy) is real — B grade.
**Olthof 2003 *J Nutr*** key RCT (n=24 healthy adults):
6 g/day TMG × 6 weeks vs placeboFasting Hcy ↓11-15%Post-meal Hcy peak ↓25-35% (the post-meal effect is bigger because protein intake produces a burst of Hcy)Fast absorption + onset: a single 6 g dose raises plasma TMG 5-10× within 1-2 hours, and Hcy drops immediately
**Olthof 2005 *Curr Drug Metab* review**:
Pooling multiple RCTs: 3-6 g/day TMG → Hcy down by 10-20% on averageMTHFR C677T carriers: down 15-30% (more significant)Effect comparable to or stronger than 5-MTHF (folate active form) 5 mg/day in some studies
**Cholewa 2018 *JISSN*** (n=23 college women, 8 weeks of resistance training):
2.5 g/day TMG: improved strength and protein-anabolic markers during resistance trainingPossible mechanisms: osmolyte cell-volume stability + indirect mechanistic target of rapamycin: The cell's master 'grow / build' switch — turned on by enough protein and resistance training. + partial Hcy reduction
Trepanowski 2011 + Lee 2010 + Hoffman 2009: small improvements in strength/power parameters with resistance training, but weak clinical significance (1-5% range).
Compared to 5-MTHF (active folate):
5-MTHF: A-grade evidence (main route), suitable for MTHFR mutation / high-Hcy general populationTMG: B-grade evidence (backup route), suitable for people already on 5-MTHF whose Hcy is still high / MTHFR carriers / high-protein diets that burn a lot of S-adenosylmethionine: The body's main methyl-group donor — it tags DNA, neurotransmitters, and more with methyl groups.Combined 5-MTHF + B12 + TMG: multi-agent Hcy-lowering trials show additive effects on Hcy, but clinical endpoint trials (myocardial infarction / stroke / death) have all failed (HOPE-2, VISP, NORVIT, VITATOPS, SEARCH) — lowering Hcy ≠ reducing cardiovascular events
This is the second appearance in the atlas of the 'mechanism perfect + endpoint null' lesson (the first was vitamin E antioxidant RCTs). The 'Hcy hypothesis' was treated in the 1990s-2000s as a causal driver of CVD, but large intervention trials have not confirmed causality. Hcy remains a risk marker, but supplementing B vitamins to lower it does not reduce hard endpoints.
**Olthof 2003 *J Nutr*** key RCT (n=24 healthy adults):
6 g/day TMG × 6 weeks vs placeboFasting Hcy ↓11-15%Post-meal Hcy peak ↓25-35% (the post-meal effect is bigger because protein intake produces a burst of Hcy)Fast absorption + onset: a single 6 g dose raises plasma TMG 5-10× within 1-2 hours, and Hcy drops immediately
**Olthof 2005 *Curr Drug Metab* review**:
Pooling multiple RCTs: 3-6 g/day TMG → Hcy down by 10-20% on averageMTHFR C677T carriers: down 15-30% (more significant)Effect comparable to or stronger than 5-MTHF (folate active form) 5 mg/day in some studies
**Cholewa 2018 *JISSN*** (n=23 college women, 8 weeks of resistance training):
2.5 g/day TMG: improved strength and protein-anabolic markers during resistance trainingPossible mechanisms: osmolyte cell-volume stability + indirect mechanistic target of rapamycin: The cell's master 'grow / build' switch — turned on by enough protein and resistance training. + partial Hcy reduction
Trepanowski 2011 + Lee 2010 + Hoffman 2009: small improvements in strength/power parameters with resistance training, but weak clinical significance (1-5% range).
Compared to 5-MTHF (active folate):
5-MTHF: A-grade evidence (main route), suitable for MTHFR mutation / high-Hcy general populationTMG: B-grade evidence (backup route), suitable for people already on 5-MTHF whose Hcy is still high / MTHFR carriers / high-protein diets that burn a lot of S-adenosylmethionine: The body's main methyl-group donor — it tags DNA, neurotransmitters, and more with methyl groups.Combined 5-MTHF + B12 + TMG: multi-agent Hcy-lowering trials show additive effects on Hcy, but clinical endpoint trials (myocardial infarction / stroke / death) have all failed (HOPE-2, VISP, NORVIT, VITATOPS, SEARCH) — lowering Hcy ≠ reducing cardiovascular events
This is the second appearance in the atlas of the 'mechanism perfect + endpoint null' lesson (the first was vitamin E antioxidant RCTs). The 'Hcy hypothesis' was treated in the 1990s-2000s as a causal driver of CVD, but large intervention trials have not confirmed causality. Hcy remains a risk marker, but supplementing B vitamins to lower it does not reduce hard endpoints.
Is MTHFR a real concern
MTHFR genotyping is one of the loudest 'genetic nutrition' marketing pitches in the supplement + integrative medicine market — but the clinical implications have been heavily exaggerated.The facts:
How common TT homozygosity (both copies carrying T) is varies sharply by ancestry — NIH ODS gives ~25% of Hispanics, ~10% of Caucasians and Asians, ~1% of African AmericansCT heterozygous: moderately reduced enzyme activityTT homozygous: the largest reductionA1298C is another common mutation with smaller effect
Real clinical impact:
Mild Hcy elevation (5-15% above wild-type)Slightly elevated folate requirement (but the standard 0.4 mg folic acid for pregnancy is usually enough)TT homozygous + very low folate intake: meaningful, but the impact is small once intake is corrected
The exaggerated parts (marketing):
'MTHFR mutation → serious health problems' — most SNP effects are subclinical'MTHFR carriers must take 5-MTHF (active folate); they can't take ordinary folate' — modern evidence (Greenberg 2011 *J Clin Lab Anal* review) shows that ordinary folic acid still works in MTHFR carriers (DHFR + alternate pathways convert it to active form); 5-MTHF's marginal advantage is small'MTHFR mutation → a full disease chain (miscarriage + autism + cardiovascular + depression)' — most associations are weak and causality is not established; the integrative medicine market oversells this
Practical:
If you've tested positive for MTHFR mutation or have a family history of high Hcy: the simple approach is to eat fortified-folate foods + eggs + leafy greens + whole wheat (TMG), or add 5-MTHF 0.4-1 mg/dayYou don't need to pay a premium for 5-MTHF or a custom TMG protocol 'because of MTHFR'TMG's real indication: already on 5-MTHF + B12 + folate but Hcy is still high; or strength training basics in place and you want to add 2.5-6 g/day as an experiment
Bottom line: MTHFR is a real genetic polymorphism, but it isn't a 'diagnosis' — it's a mild risk factor. Treat it as a risk factor, not a disease.
nih-ods-folateliew-2015-mthfr
试验清单 · 剂量、周数、降幅
TMG 降同型半胱氨酸 (Hcy) 的临床证据, 逐项:Olthof 2003 J Nutr 关键 RCT (n=24 健康成人):
6 g/天 TMG × 6 周 vs 安慰剂空腹 Hcy ↓ 11-15%餐后 Hcy 峰值 ↓ 25-35% (餐后效应更显著, 因为蛋白质摄入瞬间产生大量 Hcy)吸收 + 起效快: 单次 6 g 服用后 1-2 小时血浆 TMG 上升 5-10 倍, 同时 Hcy 立即下降
Olthof 2005 Curr Drug Metab 综述:
多项 RCT 合并: 3-6 g/天 TMG → Hcy 平均下降 10-20%MTHFR C677T 突变携带者: 下降 15-30% (更显著)效果与 5-MTHF (folate 活性形式) 5 mg/天相当或更强 (有些研究)
Cholewa 2018 JISSN (n=23 大学女性, 8 周力量训练):
2.5 g/天 TMG: 力量训练 + 蛋白合成代谢标志改善机制可能是 osmolyte 渗透压稳定 + 间接 mechanistic target of rapamycin: The cell's master 'grow / build' switch — turned on by enough protein and resistance training. + 部分 Hcy 降低
Trepanowski 2011 + Lee 2010 + Hoffman 2009: 力量训练 + 力量/功率参数微小改善, 但临床显著性弱 (1-5% 范围)
与 5-MTHF (活性叶酸) 对比:
5-MTHF: A 级证据 (主路), 适合 MTHFR 突变、高 Hcy 一般人群TMG: B 级证据 (副路), 适合 5-MTHF 已经吃但 Hcy 仍高 / MTHFR 突变、高蛋白饮食消耗大 S-adenosylmethionine: The body's main methyl-group donor — it tags DNA, neurotransmitters, and more with methyl groups.联合 5-MTHF + B12 + TMG: 多药联合的 Hcy 降低试验显示累加效应, 但真正看硬终点 (心梗、中风、死亡) 的五个大型试验全部失败 —— 降 Hcy ≠ 减心血管事件
Hcy 假说在 1990s-2000s 被当作 CVD 的因果驱动, 但大型干预试验没有验证这层因果关系。
Chapter 4
Liver fat + strength
Liver fat + strength
Beyond lowering Hcy, TMG has two secondary but real clinical signals.
1. Liver fat / NAFLD improvement
Mechanism: TMG → provides methyls → supports the PEMT pathway (phosphatidylethanolamine → phosphatidylcholine) → builds VLDL particle shell → hepatic triglyceride exportThis overlaps completely with the choline-in-NAFLD mechanism — TMG sits upstream (choline's oxidation product, also the PEMT alternate substrate)**Abdelmalek 2009 *Hepatology***: 20 g/day TMG × 1 year (no placebo, single arm) → ALT/AST drop + hepatic lipid score improvedMukherjee 2014 RCT (NASH): 20 g/day × 12 months — signal present but not reaching clinical significanceOverall evidence: B-C grade (mechanism clear, clinical endpoint weak, high dose required)
2. Strength training + body composition
**Cholewa 2018 *JISSN*** (college women, n=23, 8 weeks): 2.5 g/day TMG + resistance training → improved strength, lean mass, and training-volume metabolic markersHoffman 2009 (college male athletes): 2.5 g/day × 14 days → improved resistance-training performance indicatorsTrepanowski 2011 (trained men, n=12): 2.5 g/day × 14 days → some metabolic markers improved; small strength parameter changesLee 2010: 2.5 g/day × 1 week → improved bench press + jump power parametersTrepanowski 2011 meta + Lee 2014 review: effect size small-to-moderate (1-5% improvement), mainly in submaximal strength work
Mechanism (training performance):
Cellular osmoregulation (osmolyte): protects cell volume during training + dehydrationMethyl supply for creatine synthesis: TMG → S-adenosylmethionine: The body's main methyl-group donor — it tags DNA, neurotransmitters, and more with methyl groups. → creatine (limited contribution)Hcy reduction indirectly improves endothelial functionCortisol / androgen ratio improvements: shown in some studies, mechanism unconfirmed
Practical positioning:
TMG is not a 'miracle muscle-builder' — effect size is far smaller than creatineOn top of an already-solid base (protein + training + sleep + creatine + caffeine), 2.5 g/day TMG may add a small extra improvementNAFLD patients: assess + possibly supplement (discuss with physician; cannot replace weight management + exercise + new drugs when needed)
1. Liver fat / NAFLD improvement
Mechanism: TMG → provides methyls → supports the PEMT pathway (phosphatidylethanolamine → phosphatidylcholine) → builds VLDL particle shell → hepatic triglyceride exportThis overlaps completely with the choline-in-NAFLD mechanism — TMG sits upstream (choline's oxidation product, also the PEMT alternate substrate)**Abdelmalek 2009 *Hepatology***: 20 g/day TMG × 1 year (no placebo, single arm) → ALT/AST drop + hepatic lipid score improvedMukherjee 2014 RCT (NASH): 20 g/day × 12 months — signal present but not reaching clinical significanceOverall evidence: B-C grade (mechanism clear, clinical endpoint weak, high dose required)
2. Strength training + body composition
**Cholewa 2018 *JISSN*** (college women, n=23, 8 weeks): 2.5 g/day TMG + resistance training → improved strength, lean mass, and training-volume metabolic markersHoffman 2009 (college male athletes): 2.5 g/day × 14 days → improved resistance-training performance indicatorsTrepanowski 2011 (trained men, n=12): 2.5 g/day × 14 days → some metabolic markers improved; small strength parameter changesLee 2010: 2.5 g/day × 1 week → improved bench press + jump power parametersTrepanowski 2011 meta + Lee 2014 review: effect size small-to-moderate (1-5% improvement), mainly in submaximal strength work
Mechanism (training performance):
Cellular osmoregulation (osmolyte): protects cell volume during training + dehydrationMethyl supply for creatine synthesis: TMG → S-adenosylmethionine: The body's main methyl-group donor — it tags DNA, neurotransmitters, and more with methyl groups. → creatine (limited contribution)Hcy reduction indirectly improves endothelial functionCortisol / androgen ratio improvements: shown in some studies, mechanism unconfirmed
Practical positioning:
TMG is not a 'miracle muscle-builder' — effect size is far smaller than creatineOn top of an already-solid base (protein + training + sleep + creatine + caffeine), 2.5 g/day TMG may add a small extra improvementNAFLD patients: assess + possibly supplement (discuss with physician; cannot replace weight management + exercise + new drugs when needed)
PWO traces + LDL caveat
The TMG dose trap in pre-workout (PWO) blends (same logic as in the citrulline scene):A typical PWO scoop contains 0.5-1.5 g TMG, well below the research dose of 2.5 g/dayYou're paying for the 'advertised dose', not the 'effective dose'Buying single-ingredient TMG powder ($0.05-0.10/g) is 5-10× cheaper than PWO2.5 g TMG ≈ $0.15-0.25/day
Dose protocols:
Hcy reduction: 3-6 g/day divided (Olthof 2003 dose)Strength training: 2.5 g/day (Cholewa 2018 dose)NAFLD: 20 g/day divided (Abdelmalek 2009, high dose, needs medical supervision)
LDL side-effect warning (often overlooked):
Olthof 2005 + Schwab 2002: 6 g/day TMG may mildly raise low-density lipoprotein cholesterol: The so-called 'bad cholesterol' — the higher it is, the more plaque tends to build in artery walls. (10-15%)Mechanism is not fully clear; may be related to DMG (byproduct) → trimethylamine (TMA) → TMAO elevation (parallel to the gut TMAO pathway — see the choline story)Clinical meaning: short-term 6 g/day in healthy people is small, but people with existing cardiovascular disease / high LDL / on statins should be cautiousSolution: don't exceed 3 g/day + monitor lipids
Stacking with other methyl-related supplements:
+ 5-MTHF: synergistic Hcy reduction, but no additional liver-fat improvement (main + backup routes are independent)+ B12 (methylcobalamin): same, synergistic+ choline: upstream, dual support; but high doses of both together raise DMG / TMAO risk additively+ creatine: creatine synthesis consumes methyls → supplementing creatine spares S-adenosylmethionine: The body's main methyl-group donor — it tags DNA, neurotransmitters, and more with methyl groups. → TMG is freed for other pathways, indirectly synergistic
Safety + who shouldn't supplement:
Pregnancy / lactation: data lacking, skip (food TMG is safe)Chronic kidney disease (CKD): BHMT drops in the kidney + high TMG may add to renal metabolic burden, be cautiousDiagnosed high LDL: cap at 3 g/day + monitorMAO-A inhibitors: theoretical interaction (DMG and tyramine metabolism), be cautious
Overall: TMG is one of the most overlooked 'cheap + real + marketing-cold' molecules in the supplement aisle — in the same tier as glycine / NAC. Not revolutionary, but has real signal in the right population, and absurdly cheap.
试验清单 · 肝脂与力量训练
训练表现那几条机制:细胞渗透压调节 (osmolyte): 训练 + 脱水中保护细胞容积甲基化供应肌酸合成: TMG → S-adenosylmethionine: The body's main methyl-group donor — it tags DNA, neurotransmitters, and more with methyl groups. → 肌酸 (虽然贡献有限)Hcy 降低间接改善内皮功能皮质醇、雄激素比改善: 部分研究显示, 机制未确证
肝脏脂肪 / NAFLD —— 逐项试验:
Abdelmalek 2009 Hepatology: 20 g/天 TMG × 1 年 (无安慰剂, 单臂) → ALT/AST 下降 + 肝脂质评分改善Mukherjee 2014 RCT (NASH): 20 g/天 × 12 个月: 信号存在但未达临床显著
力量训练 —— 逐项试验:
Cholewa 2018 JISSN (大学女性, n=23, 8 周): 2.5 g/天 TMG + 力量训练 → 力量、瘦体重、训练量代谢标志改善Hoffman 2009 (大学男运动员): 2.5 g/天 × 14 天 → 力量训练表现指标改善Trepanowski 2011 (训练有素男性, n=12): 2.5 g/天 × 14 天 → 部分代谢标志改善, 力量参数微小Lee 2010: 2.5 g/天 × 1 周 → 卧推 + 跳跃力量参数改善Trepanowski 2011 (注意: 它是一项单独的交叉试验, 不是 meta): 2.5 g/天 × 14 天, 主分析里各项运动表现指标组间都没有显著差异; 只有卧推的总次数和总容量在配对比较里高了约 6.5%。也就是说, 这条线上的信号本来就靠边缘统计撑着, 别把它读成一个稳定的增益。
Chapter 5
Decision tree
Decision tree
Do you need to supplement TMG?
Q1: What is your goal / situation?
MTHFR mutation + Hcy still high (even on 5-MTHF + B12): try 3-6 g/day TMG for 8-12 weeks, recheck HcyNAFLD / fatty liver + assessment shows low choline / TMG intake: discuss the 20 g/day high-dose protocol with hepatology + nutritionistResistance training + want a marginal improvement: 2.5 g/day (Cholewa protocol)High-protein diet (>2 g/kg) + heavy training volume: high methyl consumption, TMG may give marginal benefitHealthy general person + diet already has whole grains / spinach / eggs: food covers it, no supplement needed
Q2: Dose?
Hcy protocol: 3-6 g/day dividedTraining protocol: 2.5 g/day (single or divided; pre-training is reasonable)NAFLD protocol: 20 g/day (needs medical supervision)Maintenance low dose: 1-2 g/day + TMG-rich foods
Q3: Form?
TMG powder (anhydrous betaine): cheapest, mildly sweet, dissolves well in waterBetaine HCl: this is a different molecule — it's a stomach-acid aid, containing TMG + HCl to release gastric acid; only suitable for people with low stomach acid; does not overlap with TMG's nutritional functionMultivitamins + combo products: typically contain 50-500 mg TMG, far below research dosesPre-workout (PWO): trace dose, not enough
Q4: Who shouldn't supplement:
Pregnancy / lactation: data lacking (food TMG is safe)Chronic kidney disease: BHMT drops in kidney + TMG excretion changesDiagnosed high LDL / on statins: cap at 3 g/day + monitorOn MAO-A inhibitor medication (specific drugs for Parkinson's / depression): theoretical interactionLow Hcy + food TMG already adequate: not needed
Atlas overall verdict: TMG is one of the most overlooked cheap + real-signal + marketing-cold molecules in the supplement aisle. It's not a 'new molecule' (discovered in 1866), not 'revolutionary', but in the right population it has real Hcy + strength training + NAFLD signals. At $0.15-0.25/day its downside risk is very low, and it completes the atlas's 'one-carbon metabolism dual-track' teaching with the final piece of the puzzle.
Q1: What is your goal / situation?
MTHFR mutation + Hcy still high (even on 5-MTHF + B12): try 3-6 g/day TMG for 8-12 weeks, recheck HcyNAFLD / fatty liver + assessment shows low choline / TMG intake: discuss the 20 g/day high-dose protocol with hepatology + nutritionistResistance training + want a marginal improvement: 2.5 g/day (Cholewa protocol)High-protein diet (>2 g/kg) + heavy training volume: high methyl consumption, TMG may give marginal benefitHealthy general person + diet already has whole grains / spinach / eggs: food covers it, no supplement needed
Q2: Dose?
Hcy protocol: 3-6 g/day dividedTraining protocol: 2.5 g/day (single or divided; pre-training is reasonable)NAFLD protocol: 20 g/day (needs medical supervision)Maintenance low dose: 1-2 g/day + TMG-rich foods
Q3: Form?
TMG powder (anhydrous betaine): cheapest, mildly sweet, dissolves well in waterBetaine HCl: this is a different molecule — it's a stomach-acid aid, containing TMG + HCl to release gastric acid; only suitable for people with low stomach acid; does not overlap with TMG's nutritional functionMultivitamins + combo products: typically contain 50-500 mg TMG, far below research dosesPre-workout (PWO): trace dose, not enough
Q4: Who shouldn't supplement:
Pregnancy / lactation: data lacking (food TMG is safe)Chronic kidney disease: BHMT drops in kidney + TMG excretion changesDiagnosed high LDL / on statins: cap at 3 g/day + monitorOn MAO-A inhibitor medication (specific drugs for Parkinson's / depression): theoretical interactionLow Hcy + food TMG already adequate: not needed
Atlas overall verdict: TMG is one of the most overlooked cheap + real-signal + marketing-cold molecules in the supplement aisle. It's not a 'new molecule' (discovered in 1866), not 'revolutionary', but in the right population it has real Hcy + strength training + NAFLD signals. At $0.15-0.25/day its downside risk is very low, and it completes the atlas's 'one-carbon metabolism dual-track' teaching with the final piece of the puzzle.
Complete one-carbon teaching loop
TMG completes the last piece of the atlas's one-carbon metabolism + methylation puzzle.Related stories already in the atlas:
folate/one-carbon (L4): folate → DHFR → THF → 5,10-MTHF → MTHFR → 5-MTHF (main route upstream)vitamin-b12/methylation (L4): MTR + methylcobalamin + 5-MTHF → Hcy → Met → SAM (main route)vitamin-b12/nerve (L4): MUT + adenosylcobalamin → propionyl-CoA → succinyl-CoA (odd-chain fats + BCAA)choline/membrane: PEMT pathway transfers SAM methyls to phosphatidylethanolamine → phosphatidylcholine (the main consumer)glycine/metabolic-hub: Gly is the methyl pool that SHMT pathway derives from serineniacin-b3/nad: nicotinamide adenine dinucleotide: A coenzyme that ferries electrons to drive energy production — built from vitamin B3. is the energy partner on the SAM synthesis pathTMG/bhmt-pathway (new): backup route, BHMT, doesn't depend on B12/folatespirulina/pseudo-b12-trap: real B12 vs pseudo-B12, MTR reaction failure
Full chain:
```
Dietary folate → DHFR → THF
↓
SHMT (Gly enters)
↓
5,10-MTHF
↓
MTHFR (common mutation site)
↓
5-MTHF ←──── Main route: whole body, needs B12
↓ ↓
MTR + B12 ←────── Hcy ────→ BHMT + TMG (backup: liver + kidney)
↓ ↓
Met ←─────────────────────────┘
↓
S-adenosylmethionine: The body's main methyl-group donor — it tags DNA, neurotransmitters, and more with methyl groups. ── universal methyl donor ──→
│
├── PEMT → PC (phospholipid)
├── creatine synthesis (GAMT)
├── DNA / histone methylation
├── neurotransmitters
├── detox (COMT, etc.)
└── myelin (MBP methylation)
```
This diagram cannot be fully told in any single story — it is spread across 7-8 stories, letting the user walk the atlas themselves and assemble it piece by piece.
This is the most direct embodiment of the atlas's overall product philosophy: 'knowledge about the body should be organized as a system, not a dictionary.' One-carbon metabolism isn't a single concept; it is an interconnected metabolic map, and each nutrient is a node on that map. Understanding the relationships between nodes matters far more than memorizing the names of each one.
References · 5
- Craig, S. A. S. (2004). Betaine in human nutrition. The American Journal of Clinical Nutrition, 80(3), 539-549. 10.1093/ajcn/80.3.539
- Olthof, M. R., & Verhoef, P. (2005). Effects of betaine intake on plasma homocysteine concentrations and consequences for health. Current Drug Metabolism, 6(1), 15-22. 10.2174/1389200052997366
- Olthof, M. R., van Vliet, T., Boelsma, E., & Verhoef, P. (2003). Low dose betaine supplementation leads to immediate and long term lowering of plasma homocysteine in healthy men and women. The Journal of Nutrition, 133(12), 4135-4138. 10.1093/jn/133.12.4135
- Cholewa, J. M., Hudson, A., Cicholski, T., et al. (2018). The effects of chronic betaine supplementation on body composition and performance in collegiate females: a double-blind, randomized, placebo controlled trial. Journal of the International Society of Sports Nutrition, 15, 37. 10.1186/s12970-018-0243-x
- Trepanowski, J. F., Farney, T. M., McCarthy, C. G., Schilling, B. K., Craig, S. A., & Bloomer, R. J. (2011). The effects of chronic betaine supplementation on exercise performance, skeletal muscle oxygen saturation and associated biochemical parameters in resistance trained men. Journal of Strength and Conditioning Research, 25(12), 3461-3471. 10.1519/JSC.0b013e318217d48d