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Three clinical trials were conducted in a nursing home (Day Care SKY facility in Yokohama, Japan), and their protocols and methods were described in detail (3–7). We targeted all participants (mean age around 85 years) who resided in this nursing home and required special care from a helper. They were selected by the application of the exclusion criteria before enrollment as described previously (3–5). All trials were randomized, controlled (negative or positive control), single-blinded (or double-blinded for some measurements), and parallel-group trials. Each trial had a different purpose, group, and intervention period (Table 1). Six grams of MCTs (75% C8:0, 25% C10:0) per day were mixed with foods at mealtime in all trials. This article focuses on muscle mass and function in response to MCT supplementation. Therefore, we did not describe the cognition of the subjects in detail here.

The first trial (Trial 1), which started in September 2014 and ended in December 2014 (3, 6), was conducted to find a combination of nutrients that could treat sarcopenia. The participants (n = 38) were randomly allocated to three groups: the first group received an L-leucine (1.2 g) and vitamin D (cholecalciferol, 20 μg)-enriched supplement with 6 g of MCTs (LD + MCT); the second group received the same energy-matched supplement with 6 g of LCTs (LD + LCT); and the third group did not receive any supplements (no-supplements). The supplement and oils were taken at dinner. After three months of intervention, the LD + MCT participants had increased right-hand grip strength, walking speed, 10 s leg open and close test performance, and peak expiratory flow from baseline. In contrast, no significant improvements were observed in muscle function of the LD + LCT and no-supplements groups. Therefore, it was concluded that MCTs (6 g/d) played a pivotal role in the increase in muscle function in frail older individuals.

Trial 2 started in September 2016 and ended in February 2017 (4, 7). This trial aimed to clarify whether the favorable effects observed in the LD + MCT group in Trial 1 were due to MCT itself or the interaction between MCT and LD. The participants (n = 64) were randomly allocated to three groups: LD + MCT (positive control), MCT only (target), and LCT only (negative control). Each participant’s body weight, appendicular muscle mass, and function were assessed at four equally spaced time points: baseline, 1.5 and 3.0 months after initiation of the intervention (intervention), and 1.5 months after termination of the intervention (washout). MCT (6 g/d) supplementation alone increased the muscle function of frail older individuals, suggesting that MCT oil is a responsible nutrient involved in the favorable effects of LD + MCT on muscle function observed in Trial 1.

Trial 3 started in April 2019 and ended in June 2019 (5). In Trials 1 and 2, MCTs were given at dinnertime. This study aimed to determine the suitable timing of MCT supplementation during the day. The participants (n = 40) were randomly allocated to two groups, and we compared the effects of MCTs at breakfast or dinnertime for 1.5 months. Irrespective of ingestion at breakfast or dinnertime, supplementation with 6 g MCTs/day for 1.5 months increased muscle mass and function from baseline. However, a negative control group (i.e., the LCT group) was not set because the number of participants was insufficient.

These clinical trials were approved by the Human Ethics Committee of Showa Women’s University (Nos. 14–10, 16–17, and 16–49) and by the Human Ethics Committee of Japan Society of Nutrition and Food Science (Approval No. 87). The procedures were conducted according to either the ethical standards of the institutional committee on human study or the Helsinki Declaration of 2000. Written informed consent was obtained from the participants and/or their family members in all trials.

The MCTs (75% C8:0 and 25% C10:0 from total fatty acids in oils) and LCTs (64% C18:1, 19% C18:2, and 9% C18:3 from total fatty acids in oils) were provided (Trial 1) by or purchased (Trials 2, 3) from Nisshin OilliO Group, Ltd. (Kanagawa, Japan). Six grams of MCTs (50 kcal; 8.3 kcal/g) or LCTs (54 kcal; 9 kcal/g) per day were mixed with foods such as steamed rice or miso soup at dinnertime (3, 4). The L-leucine (1.2 g) and vitamin D (cholecalciferol, 20 μg) (LD) -enriched supplement (Amino L40) was purchased from Ajinomoto Inc. (Tokyo, Japan). One tube (100 g, 30 kcal) of Amino L40 was given at the beginning of dinner (3).

The nursing care home served breakfast, lunch, and dinner daily. The individual participants’ habitual daily energy and nutrient intake during the baseline and intervention periods was calculated from data on food intakes for 7 separate days during each period using the Japanese Standard Tables of Food Composition as described previously (3–5).

Daily physical activities in this nursing home were as described previously (4). The individual daily activities and rehabilitation/exercise were not changed during the baseline and intervention periods.

The items analyzed in each trial are described in detail in the original reports (3–5), and the measurements used in this article are briefly described below.

Measurement of the right mid-upper AMA was the best approach to assess the change in muscle mass in response to MCT supplementation among the anthropometric measures we have conducted. The AMA was calculated as follows: AMA = [mid-upper-arm circumference (AC) (cm) − π · triceps skinfold thickness (TSF) (cm)]² / (4 · π) (8).

Maximal calf circumference (CC) was measured with each participant supine, with the left knee raised and the calf at right angles to the thigh. CC was used to assess calf muscle mass (9, 10).

The methods used to evaluate muscle function are restricted by the limited functional capabilities of frail older adults and the effect size of MCT supplementation. The methods that were feasible for frail older adults are described as follows.

For knee extension time, which is measured to examine muscle endurance of the quadriceps, the duration of holding each lower leg in the horizontal position was measured with the participant seated in a straight-backed chair.

For walking speed measurement, participants who could walk unaided were asked to walk for 10 m as fast as they could (3). Participants who had difficulty walking alone were asked to walk for 2.85 m with the support of parallel bars as fast as possible. Participants who could not walk for 2.85 m with the support of parallel bars used a walking aid to measure walking speed. Walking speed was calculated from the time and distance completed by each participant. The method to measure walking speed for individuals remained the same during the baseline and intervention periods.

For the leg open and close test, the number of iterations of opening and closing of the legs over a 10 s period with the participant sitting in a chair was calculated as described previously (11). Among the measurements we conducted, this test was the most sensitive for examining the impact of MCT supplementation on muscle function in frail older adults.

In people without lung disorders, peak expiratory flow was determined as an indicator of the strength of the respiratory muscles (12).

To examine the impact of MCTs relative to LCTs, the LD + MCT group was compared with the LD + LCT group (Trial 1), and the MCT group was compared with the LCT group (Trial 2). The data from Trial 3 were neither compared nor combined with others because there was no negative control group (LCT) and the intervention period was 1.5 months (the others were 3 months) (Table 1). Representative results are presented here.

Changes in measurements from baseline at the 3.0-month intervention between the MCTs- and LCTs-containing groups (combined groups from Trials 1 and 2) and their comparisons are shown in Table 2 (habitual energy and nutrient intakes), Table 3 (anthropometric measures) and Table 4 (muscle strength and functions).

Because MCT supplementation for 3 months increased muscle function similarly relative to LCT supplementation in Trials 1 and 2, irrespective of the LD supplement given (Figures 1–3), the MCTs-containing group (n = 29) was created to combine the LD + MCT group in Trial 1 with the MCT group in Trial 2; also, the LCTs-containing group (n = 27) combined the LD + LCT group in Trial 1 with the LCT group in Trial 2, and these 2 groups were compared. Thus, the MCTs- and LCTs-containing groups have a similar number of participants from Trials 1 and 2 (balanced data) and are comparable. However, participants from Trial 1 received an additional supplement of LD. To examine the possible effects of LD and the difference in the trials on the outcomes in the combined data analysis, allocation to trial (Trials 1 or 2) was adjusted for a covariate. There were almost no effects on either the changes in each group or on the difference in changes between the 2 groups for any of the measurements after additional adjustment for “allocation to trial” in the non-adjusted model in energy and nutrient intakes (Table 2) and in the non-adjusted model or model 1 in anthropometric measures and muscle function, respectively (Supplementary Tables S1, S2). However, there was an increase in the statistical power of the MCT effect with this adjustment in the measurement of peak expiratory flow: the p value of the difference in the non-adjusted changes between the 2 groups was 0.08, whereas that in the adjusted change for “allocation to trial” was 0.045; that in the adjusted change for baseline value was 0.049, whereas that in the adjusted change for baseline value and “allocation to trial” was 0.028 (the last line in Supplementary Table S2). These results suggest that the LD supplement or “allocation to trial” did not affect most outcomes but somehow affected those of the peak expiratory flow for unknown reasons. This may be one of the reasons that the significance of changes between the 2 groups in the peak expiratory flow varied in the models (Table 4).

Overall, the confounding factors we examined showed minimal effects on the outcomes (Tables 3, 4). However, an increase in left CC in the MCTs-containing group relative to the LCTs-containing group became significant after the additional adjustment of habitual energy and several nutrient intakes during the baseline period (MCTs 0.5 cm [0.0, 0.9] vs. LCTs-0.4 cm [−0.9, 0.1], p = 0.015) (Table 3). A similar tendency was observed in right CC, but this was nonsignificant (MCTs 0.4 cm [−0.1, 0.8] vs. LCTs-0.2 cm [−0.7, 0.3], p = 0.13). The following 3 covariates in model 3 contributed significantly to the change in the left CC: the estimated partial regression coefficient B for BMI at baseline was 0.324 (SE 0.092, p = 0.001); energy intake during baseline was 0.003 (SE 0.001, p = 0.039); and left CC at baseline was-0.306 (SE 0.077, p < 0.001) (data not shown). Although these mixed confounding factors may affect the outcome, their clinical significance is unclear.

Although a decrease in muscle mass is essential to the definition of sarcopenia (12), physiologically, an increase in muscle mass might not necessarily result in increased muscle strength and function. As observed in exercise training, improved functions of the mitochondria in skeletal muscles (18), neuromuscular junctions (19), and the brain (20), in addition to increasing muscle mass (i.e., increases in the number or size of type I or type II fibers) (21, 22), may increase muscle strength and function.

Kojima et al. recently reported that in healthy middle-aged and older adults (mean age 68 years old), supplementation with 6 g/day MCTs (C8:0 or C10:0) combined with moderate-intensity aerobic exercise for 3 months significantly increased muscle function (right knee extension strength) but did not alter skeletal muscle mass (overall mean skeletal muscle mass was 23 kg) compared with 6 g/day LCTs combined with aerobic exercise (23). Also, Mutoh et al. reported that supplementation with 18 g MCTs/day in healthy older adults (mean age 70 years old) for 3 months resulted in the participants showing better balance ability (one of the muscle functions) relative to those receiving a placebo (24). These findings suggested that MCTs could increase muscle function without increasing muscle mass in healthy older adults and that an increase in muscle mass by MCT supplementation might manifest in subjects whose muscle mass at baseline is very low (overall mean muscle mass was 16 kg), as is observed in frail older adults. It is also conceivable that an increase in muscle function may eventually increase muscle mass in frail older adults. However, precision in the measurement of muscle mass and functions is essential and is required for these studies.

Cognition was also improved after MCT supplementation in all trials (5–7). Therefore, improved cognition might affect muscle function (20). However, in the LD + MCT group in Trial 1, there was no significant correlation between changes in cognition test scores and changes in muscle mass and function (6). In Trial 2, the increases in peak expiratory flow and the number of swallows in 30 s persisted for 1.5 months after termination of the intervention (washout) (4). In contrast, the increases in cognition score returned to the baseline levels (7). These data suggested that the increase in cognition did not directly mediate increases in muscle function. However, it is conceivable that the motor and cognition areas in the brain were activated by a similar mechanism after MCT supplementation.

After MCT supplementation in frail older adults, slight but significant increases in body weight and muscle mass with a decrease in fat mass were observed without a concomitant increase in energy intake. These findings indicated that the energy in fat tissues might be used for muscle tissues, and an anabolic effect was seen on muscle mass. This anabolic effect is similar to that of growth hormone (GH) (25). Interestingly, there is a close relationship between MCTs and GH via ghrelin.

Activated ghrelin (acyl-ghrelin) formed by proghrelin and octanoic acid (C8:0) via ghrelin-O-acyltransferase in the stomach, enters the blood circulation and stimulates GH release in the brain (26) and GH increases muscle mass (the MCTs/Ghrelin/GH hypothesis). MCT supplementation increases blood acyl-ghrelin concentrations in humans (27–29). Supplementation with 6 g MCTs/day for 2 weeks increased acyl-ghrelin from 20 fmol/mL (baseline) to 40 fmol/mL (2-fold increase) and decreased desacyl-ghrelin (an inactive form) from 210 fmol/mL (baseline) to 160 fmol/mL in patients with anorexia nervosa (mean age, 26.4 years; BMI, 13.0 kg/m²) (28). A lower dose of MCTs was able to increase acyl-ghrelin: single oral ingestion of 3 g of MCT (100% C8:0) with enteral nutrition formula in cachectic patients increased plasma acyl-ghrelin, and the 2 weeks administration of MCTs increased appetite score, body weight, and serum albumin and insulin-like growth factor-1 (but not GH) concentrations compared with their baseline levels (27). Considering the effects of a low dose of MCTs on acyl-ghrelin concentration, acyl-ghrelin may mediate the increases in muscle mass and function in response to MCT supplementation in frail older adults. Because a decrease in GH secretion was observed with aging, MCT supplementation in older adults might be timely (30). However, it has not been shown that MCT supplementation increases GH secretion.

Many reports show that acute acyl-ghrelin injection (or infusion) increased GH concentration, appetite, and food intake and that chronic acyl-ghrelin injection increased body weight, as listed in a supplemental table of a review (31). Chronic effects of acyl-ghrelin for years are mimicked by growth hormone secretagogues receptor agonists, which require no injections. Indeed, the impact of these oral agonists on body composition has been reported in three clinical trials (32–34), all of which showed increases in body weight and fat-free mass with no change in fat mass. These data suggested that acyl-ghrelin might lead to an increase in muscle mass but not a decrease in fat mass. Because MCT supplementation decreases fat mass, other mechanisms may be involved in reducing fat mass in response to MCT supplementation.

Because in both TGCV and NLSDM (primary TGCV and NLSDM might be the same disease because the responsive gene is identical), lipid accumulation in cardiomyocytes and myocytes may cause heart failure and muscle atrophy, respectively (35, 36), MCTs, which decrease fat accumulation, have been considered a promising candidate for treating patients suffering from these conditions (37).

TGCV is a rare intractable disease in which impaired intracellular lipolysis results in massive triglyceride accumulation in the myocardium and coronary arteries, caused by genetic (primary) or acquired dysfunction of adipose triglyceride lipase (ATGL) (36). This leads to heart failure and ischemic heart disease (38). Long-chain fatty acids (LCFAs) entering cardiomyocytes are re-esterized to LCTs to form an energy pool in cells and are immediately hydrolyzed by intracellular lipases such as ATGL. In TGCV, the impaired intracellular lipolysis of LCTs results in ectopic deposition and loss of LCFA supply to mitochondria, leading to lipotoxicity and energy failure in cardiomyocytes and coronary smooth muscle cells. Because cytoplasmic MCTs were degraded at an average rate, whereas LCTs remained undegraded in fibroblasts from NLSDM patients (39), MCTs might be effective in treating TGCV. Indeed, cardiac imaging tests showed that a tricaprin diet (100% C10:0 with MCTs corresponding to 80% of total fat intake) reduced triglyceride accumulation and improved metabolism of LCFAs and left ventricular function in ATGL knockout (KO) mice compared with the ATGL KO mice fed the control diet (40). Recently, a randomized controlled MCT trial for idiopathic TGCV in humans (n = 17) was reported (41). In agreement with the results in ATGL KO mice, compared with the placebo (n = 8), supplementation with a 1.5 g/day of CNT-01 (100% C10:0) for 8 weeks (n = 9) improved myocardial lipolysis (p = 0.035) as estimated by iodine-123-beta-methyl-p-iodophenylpentadecanoic acid scintigraphy. However, decreases in TGCV severity scores (lower score indicates better outcome) between the 2 groups were nonsignificant, probably due to the short term of the intervention period. The adjusted mean changes from baseline (95% CI) were as follows: TGCV severity symptom score [CNT-01-2.78 (−4.61, −0.94) vs. placebo-0.75 points (−3.38, 1.88)] and TGCV severity ADL score [CNT-01-2.67 (−6.47, 1.14) vs. placebo-0.88 points (−3.30, 1.55)] (41).

In contrast, in a 26-year-old female patient with NLSDM caused by a mutation of ATGL without cardiac involvement, no beneficial effects on progressive muscle weakness were observed after MCT supplementation in a low-fat diet (medium-chain fatty acids [MCFAs] not specified; 30 g/day of MCTs plus 15 g/day of natural fat) for several years (42).

The difference in the effects of MCT supplementation between patients with TGCV and NLSDM might be explained as follows. (1) A high dose of MCTs was ineffective in reducing fat deposits in cells because a relatively large amount of MCT supplementation over the long term might lead to lipid accumulation in myocytes. (2) MCTs might be more effective in patients suffering effects on the heart than skeletal muscles because the heart might utilize more energy from fatty acids than the skeletal muscles do. (3) The effects of MCTs might depend on the patient’s lifestyle or environment. Therefore, there were large variations in the effects of MCTs between patients, possibly due to confounding factors. These possible effects of MCTs on muscles in patients with TGCV and NLSDM may be applied to treating sarcopenia.

This study has several limitations. We estimated muscle size by an anthropometric analysis; however, other modalities such as computed tomography, magnetic resonance imaging, and dual-energy X-ray absorptiometry may be required to confirm the results. The increase in muscle mass might reflect the accumulation of intramuscular lipids rather than an increase in muscle cell number or size; therefore, a muscle biopsy may be necessary. Critical confounding factors might have been missed. For example, ANCOVA might include individual physical activity levels as a covariate. Although a combined data analysis increased the number of participants, even more participants might be needed to observe the significant effects of MCTs in some measures relative to LCTs. Because this study targeted only frail older Japanese individuals, we should have addressed whether similar favorable effects of MCTs would be observed in Western populations with larger body sizes or non-frail subjects. Knowledge of the adverse effects of MCTs is also necessary.