Betaine Delayed Muscle Loss by Attenuating Samtor Complex Inhibition for mTORC1 Signaling Via Increasing SAM Level

Abstract

Scope The muscle loss during aging results from the blunt of protein synthesis and poses threat to the elderly health. This study aims to investigate whether betaine affects muscle loss by improving protein synthesis. Methods and Results Male C57BL/6J mice are raised from age 12 or 15 months. Mice are fed with AIN‐93M diet without or with 2% w/v betaine in distilled water as control group or betaine intervention group (Bet), respectively. Betaine supplementation to mice demonstrates better body composition, grip strength, and motor function. Muscle morphology upregulates expression of myogenic regulate factors, and elevates myosin heavy chain and also improves in Bet group. Betaine promotes muscle protein synthesis via tethering mammalian target of rapamycin complex1 protein kinase (mTORC1) on the lysosomal membrane thereby activating mTORC1 signaling. All these effects aforementioned are time‐dependent (p < 0.05). Ultrahigh‐performance liquid chromatography results show that betaine increases S‐adenosyl‐l‐methionine (SAM) via methionine cycle. SAM sensor—Samtor—overexpression in C2C12 cells could displace mTORC1 from lysosome thereby inhibiting the mTORC1 signaling. Addition of betaine attenuates this inhibition by increasing SAM level and then disrupting interaction of Samtor complex. Conclusions These observations indicate that betaine could promisingly promote protein synthesis to delay age‐related muscle loss.

Betaine Treatment Prevents TNF-α-Mediated Muscle Atrophy by Restoring Total Protein Synthesis Rate and Morphology in Cultured Myotubes

“…Moreover, betaine treatment increased the cross-sectional area of the quadricep muscle about 1.4-fold and 1.3-fold in 15- and 18-months mice, respectively. 23 Taken together, these data suggested that betaine supplementation promotes skeletal muscle differentiation and hypertrophy both in vitro and in vivo. However, in our setting, betaine had hypertrophic effect in myotubes treated with TNF-α only, showing a protective effect on inflammation-derived atrophy but not a net effect in control myotubes.…”

“…37 After 12 weeks intervention, mice treated with betaine displayed a 1.3- to 1.5-fold higher protein synthesis rate (measured by SUnSET method) than mice in age-matched control group. 23 Moreover, the same study showed that betaine increased muscle protein synthesis and hypertrophy in a time-dependent manner. 23 To treat myotubes, a concentration of 10 mM betaine has been chosen based on previous works performing dose-response on cell viability, proliferation, and differentiation of C2C12.…”

“…It has been shown that betaine promotes muscle protein synthesis via mammalian target of rapamycin complex 1 protein kinase, and this enhanced muscle hypertrophy, strength, and motor function in mice. 23 In another mice study, betaine supplementation increased muscle mass, promoted muscle formation, and regulated the ratio of fiber types in skeletal muscle. 24 Betaine promotes skeletal muscle fiber differentiation and myotube hypertrophy through the activation of the insulin growth factor-1 in vitro.…”

Homocysteine-induced endoplasmic reticulum stress activates FGF21 and is associated with browning and atrophy of white adipose tissue in Bhmt knockout mice

“…Several functional BHMT variants have been identified in humans and are associated with increased risk for cancer and other diseases [ [64] , [65] , [66] , [67] ], however, no information is available on the metabolic phenotypes of humans carrying those variants. In mice, betaine supplementation delays muscle loss in an aging model [ 68 ], and more studies are needed to investigate if this happens in humans. In a meta-analysis of randomized controlled trials, betaine supplementation is associated with reduced body fat mass and body fat percentage; however, no changes on BMI were reported [ 69 ].…”

Betaine and Soluble Fiber Improve Body Composition and Plasma Metabolites in Cats with Chronic Kidney Disease

“…Body fat was lowered with betaine supplementation [32], so the effects of betaine on body mass may depend on the species, kidney function status, and/or high metabolic demand. Betaine may exert its effect on increasing body mass by increasing protein synthesis [33] and the cell proliferation rate in regulating the cellular response to hyperosmolarity [34].…”