'Native' Whey, the Superior Whey? Transient Benefits on 'Recovery', No Size or Performance Gains in 12-Week RCT

'Natural' whey is filtered right out of skim milk, 'regular' whey from the liquid 'waste" that accumulates in the cheese production - that's at least how the scientists in the study at hand define 'natural' - in the literature 'natural whey' often refers to whey concentrate/isolate vs. hydrolysates, ie. quasi-predigested protein with a completely different peptide content.
I've discussed potential differences between 'native' whey protein and 'regular' whey protein supplements before. Unfortunately, the only evidence we've had, so far, has yet been the observation that it is digested even more rapidly than regular whey protein (learn more in my 2017 article) - a mere increase in speed, however, doesn't necessarily translate to significant, let alone practically relevant increases in muscle and/or performance gainz... without longitudinal studies, we're thus screwed when it comes to the interpretation of Hamarsland's 2017 study.

With the publication of a new study from the University Clermont Auvergne (Garcia-Vicencio 2018), data about the longitudinal effects of using 'native' vs. 'regular' whey consumption is finally available. So, let's see...
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...what Sebastian Garcia-Vicencio and colleagues actually did: They "assess[ed] if 'native' whey protein (NW) supplementation could promote recovery and training adaptations after an electrostimulation (ES) training program combined to plyometrics training" (Garcia-Vicencio 2018). More specifically, ...
  • Subjects: Forty-two young moderately active men [21.5 ± 3.2 years (mean ± SD)] volunteered to participate in the study. The study utilized an independent group design that was double-blind, randomized and placebo-controlled. Participants were randomly assigned in a block fashion, to one of three supplement groups; (1) 'native' whey (NW | n = 17), (2) standard whey (SW | n = 15), (3) iso-caloric carbohydrate placebo (PLA; n = 10). 
  • Supplementation: Participants were supplemented on only 5 days/week during a 12-week training program. Participants were supplemented with a 250-ml drink containing either 15 g of carbohydrates + 15 g of NW (Pronativ®), 15 g of carbohydrates + 15 g of standard whey protein from a cheese production process (SW group), or 30 g of carbohydrates for the PLA group (identical amount of protein, slightly higher carbs and lower fat in NW vs. SW).
    Figure 1: Amino acids composition (g) for 35 g (serving) of standard whey (SW) and 'native' whey (NW) proteins. | relative differences in SW vs. NW in the boxes (calculated based on Garcia-Vicencio 2018)
    The supplement was made from powder, diluted in water. The color, texture, and taste were similar to milk chocolate and were comparable and isocaloric between the different supplements.  Supplementation was given in a fasted state, 5 days per week at the same time of day, immediately after each training session (3/week; Monday, Wednesday, and Friday), and before breakfast, on non-training days (2/week; Tuesday and Thursday). No supplementation was given during the weekend days.
Suboptimally dosed on purpose: Are you asking yourself why the subjects were fed only 15g of whey and not 25-30 to max out the protein induced increase in protein synthesis? The scientists explain this choice very reasonably: "This suboptimal dose of protein was chosen, as recommended by Hamarsland et al. (2017), to avoid a ceiling effect in muscle protein synthesis that would have hidden any potential difference between protein qualities" (my emphasis in Garcia-Vicencio 2018).
  • Figure 2: Overview of the experimental protocol. Three testing sessions were organized before (T0), and after 6 (T1) and 12 weeks (T2) of training to evaluate the training adaptations. The recovery kinetics of neuromuscular properties were evaluated after the 1st (S1), 4th (S4), and last (S24) electrostimulation (ES) sessions.
    Training: During the first 6 weeks, the participants performed 3 ES training sessions per week. From weeks 7 to 10, one ES training session was combined w/ 2 plyometrics training sessions per week "to transfer the training adaptations into sport-specific movements" (ibid). Finally, the training volume was reduced (1 ES-training session + 1 plyometrics training session) during weeks 11 and 12 to allow tapering (Zory et al., 2010).
  • Performance Testing: To evaluate training adaptations, three testing sessions were organized before (T0), and after 6 (T1) and 12 weeks (T2) of training (Figure 1). Anthropometrical characteristics, dimensions and neuromuscular properties of the knee extensor (KE) muscles and sprinting and jumping performances were the measured outcomes. Concentric power (Pmax) was evaluated before, immediately after, as well as 30 min, 60 min, 24 h, and 48 h after the 1st, 4th and last ES training session. The maximal voluntary contraction torque (MVC), twitch amplitude, anatomical cross-sectional area (CSA) and maximal voluntary activation level (VA) were measured before (T0), and after 6 (T1) and 12 weeks of training (T2).
Now that you know everything there's to know about the study design, let's get to the results, of which I have to admit that they seem to suggest that the extra-investment you've to effect was worth it. How is that? What are the benefits? Check out Figure 3, as well.
  • Improved recovery of activation patterns: Pmax started to recover at 30 min in NW, 24 h in SW and 48 h in PLA. the adaptation kinetics in the maximal voluntary contraction (MVC) tests differed: MVC increased in NW and SW between T0 and T1, but an additional gain was only observed between T1 and T2 in NW. The voluntary activation level (VA) declined at T1 and T2 in PLA (−3.9%, p < 0.05), at T2 in SW (−3.5%, p < 0.05), and was unchanged in NW. 
  • Maximal voluntary contraction: MVC increased between T0 and T2 in NW (+11.8%, p < 0.001) and SW (+7.1%, p < 0.05), but not PLA. A corresponding increase in muscle size (CSA) was not detected - the CSA increased in all groups but did not differ between groups.
That sounds strong (literally), no? It still would be stupid to start celebrating a new goto-supplement based on these results. How come? Well, let's start with the conflict of interest statement - I quote:
"PLR, JB, MB, VV, YC, and NB are employed by Lactalis, which is the funder of the study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest" (Garcia-Vicencio 2018).
Obviously, we must not assume that the fact that six authors work for Lactalis Ingredients, the company that also founded the study, would disqualify the results as biased, let alone that the data was forged. I mean, if you wanted to make 'native' whey shine, and were willing to fabricate data, you'd probably do that in wheys... ah, ways that would yield a significant inter-group difference.
What's the mechanism for the early recovery advantage of 'native' whey? We have no idea. That's partly because the study at hand wasn't designed to elucidate the mechanism of potential inter-group differences between the NW and SW group. The scientists refer to the previously referenced increased absorption speed and higher peak values of blood leucine as potential mechanisms to explain the rather disappointing advantages of 'native' whey. I doubt that this is the relevant difference, though: I mean, let's be honest: If you hear about improved leucine levels (higher peak, reduced time to peak), you won't think about a temporary amelioration of the acute reduction in the subjects' contractile properties, but rather about increases in protein synthesis that translate to longitudinally improved muscle gains.

The term "native" is usually used to refer to (whey) protein that has not been further processed in ways that change its protein structure (fig. from Yada 2017). That's in contrast to the study at hand, where the concept of nativity refers to being from a "natural" vs. "processed" (How much more 'natural' is skim milk compared to cheese whey, anyway?) raw material.
Since the amino acid make-up of Pronativ® (Lactalis Ingredients, BourgbarrĂ©, France), a 95% (on dry basis) soluble milk protein isolate, didn't differ much from that of the standard whey protein, we will have to consider other potential mechanisms. Of these, differences in the amount and type of functional peptides or other nutrients between 'native' and standard whey are imho the most likely reasons for the neuromuscular resiliance of the subjects who consumed the 'native' whey that's produced directly from skimmed cow milk by "a mild physical separation membrane process" (quote from the paper, not from an ad ;-), not from residues of the cheese-making process.

I couldn't find evidence to support this hypothesis, though. Mostly because the term "native whey" is used inconsistently in the literature and usually refers to whey concentrate vs. hydrolysate, instead of distinguishing whey proteins according to their raw materials (see the figure from Yada 2017 and my caption on the left).

What I can tell you, though, is that "native whey" - in the sense of the study at hand, i.e. whey made from skim milk (SM) - and whey protein that's produced based on buttermilk differ significantly (Svanborg 2015) in terms of their casein nitrogen content (higher in SM | +155%), total fat (lower in SM | -91%), calcium (higher in SM | +15%), iron (lower in SM | -45%), magnesium (lower in SM | -66%), phosphatidylcholine (lower in SM | -86%), and lysophosphatidylcholine (higher in SM | 385%) concentrations.

Difference in macro-mineral content of different types of whey protein (buttermilk, 'native', concentrate, isolate) expressed as rel. difference to the mean for each mineral (based on Svanborg 2015, Whetstine 2005).
Unfortunately, I couldn't find a direct comparison involving whey concentrate and isolate, as well as 'native' whey (i.e. whey that was extracted directly from skim milk). To still illustrate what one would have to do to identify potential nutritional confounders I've combined data from Svanborg et al. 2015 with averages I calculated based on Whetstine et al 2005 to plot the relative differences in lactose, fat and macro-mineral content (with the control supplement in the study being a cheese-whey based isolate, the only difference that is pronounced enough would be the calcium content... and while calcium plays a role in neuromuscular facilitation (Katz 1968), it is imho unlikely that it is the only and decisive advantage of 'native' whey.

Eventually, we obviously need much more data (e.g. peptide-structure, phospholipids, etc.) from std./identical tests to make valid predictions about a potential nutrient-related mechanism behind the pro-regenerative effects of 'native' whey. In the meantime, we can probably console ourselves by reminding ourselves that the real-world advantage is marginal, anyway.
What I am asking myself, though, is whether the scientists really chose to present the relevant results only in relative, not in absolute terms (not even in additional tables). Was that really just "[f]or the sake of clarity" as they write in one of the captions. As I've previously emphasized for my own figures, graphs that plot the relative changes are indeed often easier to read, but they also tend to (over-)emphasize inter-group differences.
Figure 3: The only significant differences between 'native' whey (NW) and standard whey (SW) were detected in the maximal voluntary activation (that's not MVC!) and concentric power tests after 12 weeks and after the first 4 EMS sessions (my markup in Garcia-Vicencio 2018); all other tests failed to show significant advantages of 'native' over standard whey..
Speaking of which, significant inter-group differences were observed only for the change in the subjects' maximal voluntary activation level after 12 weeks (T2 | tested separately from regular workouts at least 24h after the last intense physical activity) and their change in concentric power right after the fourth EMS session. The practical relevance of these changes is questionable, but the scientists are right when they interpret this observation as evidence "that the NW group better coped with the physical demand of the training program during the first weeks" (Garcia-Vicencio 2018). In that, Garcio-Vicensio et al. probably mean that the neuromuscular impairments (note: that's not the real world athletic performance or the actual contractile force, which would be voluntary contraction, not voluntary activation) due to an intense, novel exercise stimulus such as the first EMS sessions in weeks 1-2 and the additional sprint and jump training in weeks 7-8 were ameliorated by the 'native' whey supplement.

A real-world performance (sprint or jump performance) or pro-anabolic effect in terms of increased muscle gains, which are obviously the changes people would be willing to pay for, was not observed in the study at hand. More specifically, the 12-week changes in sprint (-1.6% faster) and jump performance (+2.4% power during squat jumps), as well as knee extensor cross-sectional area (+8.3% CSA after 12 weeks) were identical for all three groups.

Lastly, I shouldn't forget to mention that there were no differences in markers of muscle damage - and that in spite of the previously described neuromuscular effects of 'native' vs standard: Neither the subjects' subjectively rated DOMS nor the CK-levels showed significant inter-group differences (for all three treatments) - a result that is consistent with the results of the majority of protein supplementation studies, and excludes another potential mechanism behind the ameliorated neuromuscular impairment in response to intense, novel exercise stimuli.
Suggested SuppVersity Classic Article: "Protein-Timing & Fasting: Fasted Sprints & the Remarkable Muscle↑, Fat↓ Effect of Timing Whey With vs. Between Meals" | read more.
Probably not worth the extra money!? When the scientists write in the discussion that "the differential effects of the supplements were particularly clear when considering the recovery kinetics of the concentric power" (Garcia-Vicencio 2018) that is, to say the least, 'ambiguous'. What the scientists should have written was not that the evidence was "particularly clear" for these parameters but that significant inter-group differences between the NW and SW groups existed only for two measures of the recovery kinetics - and, more specifically, only for the temporary maximal voluntary activation and the acute concentric power measured right after a bout of (at that time) still unaccustomed EMS.

Don't get me wrong, I don't want to trivialize these benefits, but it must be emphasized that the previously mentioned change in concentric power after an acute bout of electrical muscle stimulation rebounded after an initial adaptation phase and ended up being non-significantly higher in the standard (SW) vs. 'native' whey (NW) group (~18% vs. ~11% | see Figure 3). With the maximal voluntary activation being a rather theoretical advantage (if it doesn't result in greater force production as in the study at hand), this leaves us without any significant practical advantage in the long run, i.e. when the subjects have ample time to adapt!

Using casein protein pre-bed can be useful but probably only for those of us who cannot eat enough protein over the course of the day and use it to up their total protein intake | learn more.
Hence, any potential advantage of 'native' over standard whey is most likely to occur in the very beginning of the adaptation period and will materialize in form of an amelioration of temporary performance declines that occur in response to the unaccustomed muscular strain of starting a new workout program -- here, an EMS workout program the scientists chose because it is known to "generate[] recovery issues and potential blunted training adaptations" (Garcia-Vicencio 2018) that won't occur in response to either the strength & hypertrophy routine the avg. gymgoer is following or the progressive intense sprint training a pro-athlete may have been doing for years.

The study found no extra muscle gains, no performance increments, and also no reductions in delayed onset muscle soreness (DOMS) and, at best, 'measurable', but practically irrelevant changes in muscle activation patterns. Eventually, I would thus venture the guess that you, just like the subjects in the study at hand, wouldn't feel or see any benefits if you switched from your 20€/kg standard whey isolate to a 'native' whey isolate that will cost you 27€/kg and hence a premium of 35% (price estimated based on randomly selected 'native' (=Pronativ® based) vs. regular whey products on the European market) | Comment on Facebook!
  • Garcia-Vicencio, Sebastian, et al. "A moderate supplementation of native whey protein promotes better muscle training and recovery adaptations than standard whey protein–a 12-week electrical stimulation and plyometrics training study." Frontiers in Physiology 9 (2018): 1312.
  • Hamarsland, HĂ„vard, et al. "Native whey induces higher and faster leucinemia than other whey protein supplements and milk: a randomized controlled trial." BMC Nutrition 3.1 (2017): 10.
  • Katz, Bo, and R. Miledi. "The role of calcium in neuromuscular facilitation." The Journal of Physiology 195.2 (1968): 481-492.
  • Svanborg, Sigrid, et al. "The composition and functional properties of whey protein concentrates produced from buttermilk are comparable with those of whey protein concentrates produced from skimmed milk." Journal of dairy science 98.9 (2015): 5829-5840.
  • Whetstine, ME Carunchia, A. E. Croissant, and M. A. Drake. "Characterization of dried whey protein concentrate and isolate flavor." Journal of dairy science 88.11 (2005): 3826-3839.
  • Yada, Rickey Y., ed. Proteins in food processing. Woodhead Publishing, 2017.
  • Zory, Raphael F., Marc M. Jubeau, and Nicola A. Maffiuletti. "Contractile impairment after quadriceps strength training via electrical stimulation." The Journal of Strength & Conditioning Research 24.2 (2010): 458-464.
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