A High-Fat Diet Aggravates the Age-Related Decline in Skeletal Muscle Structure and Function

Hans Degens; Anandini Swaminathan; Jason Tallis


Exerc Sport Sci Rev. 2021;49(4):253-259. 

In This Article

Methionine Restriction to Reduce HFD-induced Skeletal Muscle Dysfunction

Dietary interventions are often used in combination with exercise to combat the negative effects of HFD-induced obesity. In old obese individuals, it is especially important to focus on reducing adiposity and increasing skeletal muscle mass to improve quality of life.

Calorie restriction or dietary restriction attenuates sarcopenia,[32] and a combination of calorie restriction and exercise increased m. plantaris cross-sectional area in aged rodents[33] compared with those on an ad libitum diet. Although calorie restriction yields desirable results, limiting calorific intake over a long time is challenging and not sustainable.[34]

Methionine restriction has been described as a calorie restriction mimetic and has been found to extend lifespan and reduce age-related inflammation in rats.[35] Recent research has demonstrated that restricting methionine to 0.17%–0.25% from the normal 0.86% is the ideal range to elicit metabolic benefits without stunting growth in young-adult mice.[36] In practical terms, methionine restriction can be achieved by switching to a vegan diet as foods like fruits, vegetables, legumes, nuts, and soy contain relatively low quantities of methionine compared with animal products.[37]

Increased adiposity, insulin resistance, and mitochondrial degradation are some of the metabolic outcomes of sarcopenic obesity. Although hyperphagia has been reported in mice on methionine restriction, it nevertheless induced a 30%–50% decrease in body mass and fat mass.[35,38] This reduction in fat mass despite hyperphagia was related to an increase in energy expenditure and fat oxidation, and decreased insulin resistance.[34,36] Part of this is attributable to a shift in fuel utilization to lipids as seen after 16 wk of methionine restriction in obese people.[34]

One of the mechanisms underlying the increased energy expenditure during methionine restriction may well be a rapid and persistent increase in the expression of uncoupling protein 1 (UCP1) as seen in adipose tissue of rats and mice, and increased circulating adiponectin and decreased leptin levels.[34,39] The elevated levels of circulating adiponectin preserve or restore insulin sensitivity by lowering muscle triglycerides by oxidation of free fatty acids.[39] Although these observations were made in nonobese old rats,[39] they bear promise to combat obesity in old age.

The increase in plasma adiponectin, decrease in leptin, and up-regulation of fibroblast growth factor 21 (FGF21) in mice fed a combination of methionine restriction and HFD,[38] and obese mice on methionine restriction[40] was associated with protection against obesity and insulin resistance. The latter study[40] also reported elevated levels of circulating FGF21 in humans on a vegan or vegetarian diet, typically low in methionine. In addition, it was shown in adiponectin, FGF21, and double knockout mice[41] that the methionine restriction-induced reduction in adipose tissue in obese mice was associated with elevated lipolysis, apoptosis, and autophagy and can occur independent of circulating levels of adiponectin and FGF21.

The methionine restriction-induced lypolysis and shift to fatty acid oxidation may be related to the increased secretion of adiponectin by adipose tissue and skeletal muscle that has been linked to enhanced transcription of PGC1α in skeletal muscle.[42] PGC1α promotes mitochondrial biogenesis and enhances thereby the capacity for fatty acid oxidation.[43] This is significant, as age-associated mitochondrial dysfunction is an important factor in sarcopenia.[44] Furthermore, the accumulation of intramuscular fat reduces phosphorylation of targets in the mTOR-AMPK pathways that can lead to anabolic resistance[45] and, hence, the risk of sarcopenia.[21] Amino acid restriction has been found to enhance production of H2S via the transsulfuration pathway that activates AMPK in the skeletal muscle[46] and up-regulates SIRT1,[47] which both increase expression of PGC1α.[43] In addition, the increased expression of PPARδ in the skeletal muscle of young-adult methionine-restricted rats[48] can induce transcription of PGC1α in skeletal muscle[49] and hence further enhance mitochondrial biogenesis. In addition to stimulating mitochondrial biogenesis, methionine restriction has also been shown to reduce mitochondrial oxidative DNA damage and to lower membrane unsaturation in rat brain.[50] Although further research is required to fully elucidate the effect of methionine restriction on IMCL and skeletal muscle lipid metabolism, methionine restriction shows promise in being able to enhance lipolysis in skeletal muscle via PGC1α-controlled mitochondrial biogenesis that is prompted by up-regulation of AMPK and SIRT1.