Can uneven protein distribution negatively affect muscle gain? Original paper

In this randomized controlled trial in older adults, an even distribution of protein intake throughout the day resulted in greater net whole-body protein balance compared to an uneven distribution.

Whether the distribution of daily protein intake influences net whole-body protein balance (the primary outcome) and muscle protein synthesis (MPS) rates.

24 older adults (ages 65 to 80, 12 men and 12 women) without known health conditions.

In this 10-day randomized controlled trial, the participants consumed 1.5 grams of protein per kilogram of lean body mass per day. Protein intake was divided in 1 of 2 ways:

• EVEN: 30% of protein intake was consumed at each of the 3 main meals
• SKEWED: 15% of protein intake was consumed at breakfast, 15% at lunch, and 60% at dinner

Total energy intake in the meals was equal in both groups, and the fat content was identical (31% of energy) in all meals in both groups. During the initial 7 days, all foods were delivered to the homes of the participants. In the following 3 days, all foods were prepared and eaten at the research ward.

A trial day then took place in which the participants consumed their respective diet and laid or sat in a bed for the entire day, with the exception of two bouts of 15 minutes of cycling. At 8 a.m., a primed continuous infusion of ²H₈-phenylalanine and ²H₂-tyrosine (tracking agents) was initiated. The researchers collected blood samples over 11 hours to measure whole-body protein turnover and muscle biopsies from the vastus lateralis to measure MPS rates over 9 hours.

Whole-body protein breakdown was higher in SKEWED than in EVEN at 285–345 minutes and 430–555 minutes, and the overall area under the curve of the 11-hour postprandial (postmeal) period for whole-body protein breakdown was higher in SKEWED than EVEN. There were no clear differences in whole-body protein synthesis between groups. Consequently, net whole-body protein balance was more positive in EVEN than SKEWED.

There was no difference between groups for MPS.

Sarcopenia is a progressive and generalized skeletal muscle disorder characterized by a loss of muscle mass and strength.^[1] It is one of the greatest health concerns for older people because it is associated with an increased risk of adverse outcomes such as physical disability and mortality.^[2] Therefore, preserving or attenuating the decline in muscle mass with aging is of the utmost importance for maximizing health outcomes in older adults.

The status of muscle mass is based on the dynamic balance between MPS and muscle protein breakdown (MPB). When the rate of MPS is less than MPB, net muscle protein balance is negative. If this negative balance is sustained over time, a loss of muscle mass occurs. Besides resistance exercise, the most potent stimulator of MPS is dietary protein ingestion.

Evidence suggests that in older adults, a protein bolus of roughly 0.40 grams per kilogram of body mass is needed, on average, to maximally stimulate MPS at rest, but some individuals may need as much as 0.60 grams per kilogram of body mass.^[3] Additionally, consuming a moderate dose of protein every 3 hours has been shown to result in greater MPS rates throughout the day than consuming a low dose of protein every 1.5 hours or a large dose of protein every 6 hours.^[4][5]

In combination, the above indicates that MPS is a saturable process, meaning that there is an amount of protein that maximally stimulates MPS, and the consumption of a greater amount of protein will not further increase MPS rates and the building of muscle proteins. Additionally, a sufficient bolus of protein should be consumed every few hours to maximize daily MPS rates.

Therefore, an even distribution of dietary protein ingestion should result in a more positive net muscle protein balance, resulting in a better preservation of muscle mass with aging, because a maximal stimulation of MPS will be achieved more frequently. In support of this hypothesis, observational studies have reported a positive association between an even protein distribution and muscle mass.^[6]

In contrast, whole-body protein synthesis and MPS rates did not differ between groups in the summarized study. Similarly, a 2015 study reported that MPS rates did not differ between groups of older adults who consumed 1.5 grams of protein per kilogram of body weight per day in either an even (33% of daily protein intake at each main meal) or uneven (15% of daily protein intake at breakfast, 20% at lunch, and 65% at dinner) distribution pattern.^[7]

So, does an even distribution of daily protein intake maximize daily MPS rates or not? What’s the reason for these seemingly contradictory findings? A key difference between these studies is the source of protein consumed.

In the 2 studies (including the summarized one) that found similar daily MPS rates between even and skewed protein distributions, the participants consumed whole food meals, whereas in the other studies, including those that examined the dose of protein needed to maximize the MPS response, milk or whey protein supplements were consumed in isolation.

The food matrix, which is the nutrient and nonnutrient components of foods and their molecular relationships to each other, plays a role in the differences between these results. Alongside the structure of the protein source in question and whether the protein is consumed alongside other foods and nutrients, the food matrix has been shown to affect the absorption rate of amino acids and peak levels of amino acids in the blood.^[8][9][10] For example, the absorption rates of whey protein and cooked egg protein have been estimated at 10 and 3 grams per hour, respectively.^[11] As such, the absorption of 20 grams of protein derived from whey protein would take approximately 2 hours, whereas it would take about 7 hours from cooked egg. As speculated by the authors of the summarized study, “when protein is ingested as part of a mixed meal, the peak MPS response could be lower and more prolonged with less impact of an EVEN or SKEWED distribution pattern.”

Due to the currently scant body of evidence on the topic, further studies implementing whole food meals are needed to confirm whether daily MPS rates differ between even and skewed protein distribution patterns in older adults. Nevertheless, the results of the summarized study suggest that even if it is indeed the case that daily MPS rates do not differ between protein distribution patterns, there may still be an advantage to an even distribution pattern, namely, by promoting a greater reduction in whole-body protein breakdown, thus resulting in a more positive net whole-body protein balance.

However, it must be highlighted that net whole-body protein balance is not the same as net muscle protein balance. Whole-body protein measures provide a holistic assessment of systemic changes in multiple body protein pools, including skeletal muscle, as well as splanchnic (pertaining to the gut) and organ proteins.

The body doesn’t use dietary protein only to make skeletal muscle. Following protein ingestion, approximately 50% of available amino acids are taken up by the gut and liver for the purposes of energy production and local protein synthesis.^[12] The remaining amino acids are partly used for MPS, but ultimately serve as substrate for an array of metabolic processes, from urea synthesis to neurotransmitter production.^[12]

Whole-body utilization of ingested protein at rest

Adapted from ^[12].

The body’s capacity to digest and absorb dietary protein far exceeds that of skeletal muscle’s capacity to utilize amino acids for muscle anabolism. In contrast to studies that examined the dose-response effects of protein ingestion on MPS and demonstrated a plateau in MPS rates beyond the ingestion of a certain amount of protein, studies that examined the dose-response effects of protein ingestion on net whole-body protein balance suggest there is no practical limit to the total anabolic response to dietary protein ingestion. This is an important relationship because total anabolic response relates to both whole-body and muscle protein synthesis and breakdown.^[13]

For example, studies that compared the consumption of 70 or 40 grams of protein from lean beef reported that net whole-body protein balance was more positive with 70 grams of protein,^[14][15] primarily due to a greater suppression of protein breakdown. Furthermore, in another study by the same group, incrementally higher protein intakes (from about 6 to 92 grams of protein) led to greater whole-body net protein balance.^[7]

Muscle protein constitutes approximately 40% of the whole-body protein pool, and it’s thought that muscle protein turnover constitutes 35%–50% of the whole-body protein turnover rate.^[16] Consequently, it’s not possible to discern whether the reduced rates of protein breakdown in the EVEN group were largely driven by a decreased breakdown of muscle protein. It may be surmised that a decreased breakdown of muscle proteins at least partially contributed to the more positive whole-body net protein balance in the EVEN group, though this effect cannot be known for certain.

How daily protein intake is distributed is much less important than consuming enough overall protein throughout the day in the first place,^[17] but that doesn’t mean protein distribution doesn’t matter at all. Further research is needed to elucidate whether an even distribution of daily protein intake decreases the breakdown of muscle proteins, as well as if even distribution improves health outcomes in older adults, such as ensuring a better preservation of muscle mass and physical function, resulting in a reduced risk of adverse health outcomes.

In the meantime, it’s recommended that older adults eat protein at least 3–4 times per day, approximately 3–5 hours apart, consisting of 0.4–0.6 grams of protein per kilogram of body mass to help preserve muscle mass during aging.^[17]

The participants in the summarized trial were more or less confined to bed on the trial day, so the results may differ in the context of high levels of physical activity.