Friday, July 15, 2016

Carbs, Leucine-Rich Whey or Soy +/- HMB - What's Best to Protect Muscle From Catabolism During an Extended Fast?

I still believe that the ill effects of fasting on skeletal muscle are way overrated, but I guess it won't hurt if you would be able to minimize it by sipping 60g of protein, right? A new study says: That's right, but there's more to it.
While the beneficial effects of whey protein and leucine have been shown to be independent of age and route of administration in anabolic conditions, there is, as scientists from Aarhus University Hospital point out, almost no information "about the effects of leucine-rich protein supplementation to humans during catabolic conditions such as fasting" (Rittig. 2016).

This is however, only partly right. From previous articles here at the SuppVersity you know that studies investigating the effects of protein supplements on muscle protein maintenance exist and that the effect is - due to increased wastefulness - less pronounced than you probably hoped for.
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Rittig et al. are right though, when they criticize that these studies failed to "include comparisons to other conventional nutrients and did not assess specific effects on muscle protein kinetics and signaling events" (Rittig. 2016). Needless to say that the Danish researchers tried to fill this gap in our knowledge about the anti-catabolic effects of different proteins and designed a study to test (i) whether a leucine rich (~16% of total protein content) whey protein beverage is more anabolic in muscle under catabolic conditions compared with isocaloric carbohydrate, and isocaloric isonitrogenous soy protein with and without 3 g HMB enrichment and (ii) whether leucine-rich whey protein specifically affects regulators of protein-synthesis and breakdown in muscle.
Figure 1: Study design and composition of the test drinks (Rittig. 2016).
The actual study design looked as follows: In a randomized crossover-trial with four different study days, each study day was separated with a minimum of 21 days. The subjects, 8 healthy young men (median age of 24 years, range 21-34 years; median BMI of 25 kg/m², range 20-30 kg/m²; and median body weight of 88 kg, range 67-106 kg) were blinded to the intervention and were "thoroughly instructed only to drink tap water ad libitum 36 h (total fasting with absolutely no calorie intake allowed) preceding each trial," which started at 7:00 AM and during which the subjects consumed one of the following treatments (Figure 1):
  • a beverage containing carbohydrate (CHO)
  • a beverage based on leucine-rich whey protein (LWH)
  • a beverage based on soy protein (SOY)
  • a beverage based on soy protein + 3 g HMB (HMB)
The effects of the intervention were assessed by analyzing muscle biopsies that were obtain vastus lateralis of the subjects' quadriceps muscle during the fasted period (time = 60 min) and during the sipping period (time = 380 min). Thus, there were 120 minutes between the initial muscle biopsy and the consumption of the first third of the test beverage at t = 180 min and another 180 min during which the test-subjects drank smaller portions of the beverage every 20 min before the final muscle biopsy (Note: 40 of the 60g of protein were "sipped", because the scientists wanted to avoid potential gastrointestinal problems with 60g protein being consumed at once, not because they thought that this will (a) maintain the beneficial effects of fasting or (b) be more anabolic than bolus ingestion).
Figure 2: Isotopic 15N-phenylalanine was used in a forearm model to investigate the net balance- (A), rate of appearance- (B), and rate of disappearance (C) of phenylalanine during the sipping period for the carbohydrate (CHO)-, leucine-rich whey protein (LWH)-, soy protein (SOY)-, and soy protein + 3 g HMB (HMB) group (Rittig. 2016).
Even though the scientists assessed a whole host of parameters, including the energy expenditure and how fat, protein and carbohydrates contributed to the latter (see Figure 3), the net muscle protein loss (measured as the net balance of phenylalanine, NBphe), muscle protein breakdown (measured as phenylalanine rate of appearance, Raphe), and muscle protein synthesis (measured as phenylalanine rate of disappearance, Rdphe) are unquestionably the most significant study results. Results that did not differ between groups after 36 h of fasting, but - at least for two of them - showed quite significant differences during the sipping period where...
  • NBphe improved in all groups but more so for LWH and HMB compared with SOY (One-way repeated measure ANOVA, p < 0.05), 
  • Raphe decreased for CHO, LWH, and SOY in the sipping period compared with the fasting period (p < 0.05) but without any differences between groups. 
Interestingly enough, the Rdphe numbers did not change between the fasting and sipping periods and did thus also not differ between groups (as the scientists point out this could be due to the "muscle full" effect, because the protein flux was assessed late in the study).
Figure 3: Total energy expenditure during fast (baseline) and while sipping the beverages expressed in kcal of oxidized protein, glucose and lipids; %-ages indicate rel. difference to baseline (Rittig. 2016)
Still, the urea fluxes which did not differ between groups after 36 h of fasting (average 384 ± 17 mmol/kg/hour), but differed significantly during the sipping period (one-way repeated measure ANOVA, p ¼ 0.009), as CHO (330 ± 20 mmol/kg/hour) was significantly lower than LWH (408 ± 24 mmol/kg/hour), SOY (412 ± 19 mmol/kg/hour), and HMB (469 ± 38 mmol/kg/hour) clearly reflect that the protein oxidation was increased by consuming protein / HMB (compare Figure 3).

Overall, it is thus clear that leucine-rich proteins like whey and/or its metabolite HMB can (a) help you preserve lean muscle mass while fasting and (b) will do this more effectively than soy or carbohydrates which are not useless, but at least less effective. In that it may be worth highlighting that simply adding HMB to soy protein can change that, even though it did not have the mTOR-increasing effects the scientists expected HMB to have. Practically speaking, this means that the study at hand confirms that HMB works, but does not provide an explanation for the mechanism by which "HMB exerts its anabolic effect in human muscle" (Rittig. 2016) - after all, the soy + HMB treatment triggered a sign. decrease in muscle breakdown, even though it was not more successful in boosting mTOR than both the soy and the likewise ineffective carbohydrate treatment and in spite of no significant difference in the expression of catabolic protein signals.
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Bottom line: So, while the study at hand demonstrates the relatively profound anti-catabolic effects of sipping 63.7g of protein during total fasting, its practical implications would have to be tested in the long(er) run to know how much muscle mass this could effectively spare and whether and which of the multiple benefits of fasting may be impaired, when you consume ~20g of protein at once and the rest of it within 120 minutes during a fast (BCAAs alone have been shown to impair autophagy, an important physiological process by the means of which your cells are kept in homeostasis and functioning by protein degradation and turnover of the destroyed cell organelles for new cell formation, in rodents | Naito. 2013).

This, as well as the previously hinted at lack of evidence regarding the mechanism by which HMB adds to the quasi non-existent benefits of soy protein require future investigations... it is not, as the lack of difference in muscle atrophy markers like FoxO3a, MURF1, and FBX32 shows, due to its previously observed effects on the phosphorylation and contents of these proteins in rodent studies (Baptista. 2013; Noh. 2014) | Comment!
  • Baptista, Igor L., et al. "Leucine and HMB differentially modulate proteasome system in skeletal muscle under different sarcopenic conditions." PloS one 8.10 (2013): e76752.
  • Naito, Takako, Akiko Kuma, and Noboru Mizushima. "Differential contribution of insulin and amino acids to the mTORC1-autophagy pathway in the liver and muscle." Journal of Biological Chemistry 288.29 (2013): 21074-21081.
  • Noh, Kyung Kyun, et al. "β–Hydroxy β–Methylbutyrate Improves Dexamethasone-Induced Muscle Atrophy by Modulating the Muscle Degradation Pathway in SD Rat." PloS one 9.7 (2014): e102947.
  • Rittig, Nikolaj, et al. "Anabolic effects of leucine-rich whey protein, carbohydrate, and soy protein with and without β-hydroxy-β-methylbutyrate (HMB) during fasting-induced catabolism: A human randomized crossover trial." Clinical Nutrition (2016).