Running on empty: The physiological consequences of underfueling Original paper

In this randomized controlled trial in physically active women, 10 days of low energy availability decreased daily muscle protein synthesis rates, resulting in a loss of lean mass.

The effect of low energy availability (LEA) on muscle protein synthesis.

LEA is a state in which energy intake is insufficient to cover the energy costs of both energy expenditure from exercise and basic physiological functions.

Both myofibrillar (involved in muscle contraction) and sarcoplasmic (involved in mitochondrial activity and enzymatic function) protein synthesis were measured daily via deuterium oxide consumption. The other outcomes assessed were body composition, whole-body nitrogen balance, resting metabolic rate, and levels of thyrotropin, triiodothyronine (T3), glucose, insulin, cortisol, testosterone, and sex hormone binding globulin.

30 women (ages 18–30) who had a regular menstrual cycle and exercised between 4 and 10 times per week, including at least one resistance and one aerobic exercise session per week.

The intervention started 1–5 days after the first day of menstrual bleeding. All of the participants underwent a 5-day run-in period with optimal energy availability (OEA, 50 kcal per kg of fat-free mass per day). For the next 10 days, the participants were randomly assigned to continue with OEA or LEA (25 kcal per kg of fat-free mass per day).

Throughout the intervention, all of the participants consumed 2.2 grams of protein per kilogram of lean body mass per day and performed a supervised resistance and cardiovascular exercise program. In addition, the participants were provided with all foods based on their individualized meal plans.

Compared to OEA, daily rates of myofibrillar and sarcoplasmic protein synthesis decreased in LEA. Nitrogen balance also decreased (via an increase in nitrogen excretion) in LEA compared to OEA.

Body weight remained stable in OEA, whereas it decreased by 1.7 kg in LEA. In LEA, fat mass decreased by 1.3 kg and bone-free lean mass decreased by 0.4 kg, whereas in OEA, lean mass increased by 0.4 kg and fat mass decreased by 0.5 kg. Resting metabolic rate also decreased in LEA compared to OEA (−65 kcal vs. no change).

In terms of blood biomarkers, levels of thyrotropin, T3, and glucose decreased, and levels of sex hormone binding globulin increased in LEA compared to OEA.

Energy availability (EA) is defined as the difference in energy intake and exercise energy expenditure relative to fat-free mass (FFM). For example, consider a person with 70 kg of FFM who has a total daily energy intake of 3,000 kcal and an exercise energy expenditure of 750 kcal. This would leave 2,250 kcal left over, which, divided by their FFM, results in an EA of about 32 kcal/kg of FFM.^[1]

LEA refers to a state where energy intake is insufficient to cover the energy costs of both exercise energy expenditure and basic physiological functions, which triggers acute endocrine, metabolic, and physiological dysregulations.^[2]

Note that EA is different from energy balance. EA is focused on the relationship between energy intake and exercise energy expenditure, with reference to the amount of energy remaining to maintain physiological function outside of exercise. Ideally, an individual’s energy intake would not only be sufficient to fuel exercise, but also recovery and exercise-induced adaptations, as well as the functions required by the body to maintain optimal health.

Energy balance considers all components of energy expenditure, including exercise energy expenditure, resting metabolic rate, and the thermic effect of food. It is typically used in the context of changes in body weight. EA and energy balance are related but fundamentally different concepts. For example, LEA and weight loss are associated with one another,^[2] but an individual can be weight stable and not have excessively low body fat levels and still suffer adverse physiological effects induced by LEA.^[3] Alternatively, an individual could be in negative energy balance, but still have sufficient energy availability to avoid LEA.

LEA is caused by insufficient energy intake and/or excessive exercise energy expenditure. Much of the literature on this topic considers an EA of 30 kcal per kilogram of FFM per day or less as LEA for women,^[4][3] as evidenced by unfavorable alterations in markers of bone turnover and metabolic (e.g., leptin, T3, cortisol) and reproductive hormones (e.g., estradiol, luteinizing hormone) when this threshold is surpassed. In men, a recent study provided evidence of a threshold of approximately 17 kcal per kg of FFM per day.^[5]

The reported prevalence of LEA is relatively high among athletes, especially female athletes. The exact prevalence varies between studies, which is due to differences in assessment methods and the time point when the participants were assessed (i.e., off-season vs. pre-season vs. in-season), among other factors. Additionally, most of the studies included small sample sizes, so the results should be taken with a grain of salt. Nonetheless, it’s been reported that the prevalence of LEA, either as indicated by dietary intake or common signs of the condition (e.g., menstrual dysfunction), is approximately 31%–64% in endurance sports,^{[6][7][8][9][10]} 45% to upward of 100% in gymnasts,^[11][12], 53% in cheerleaders,^[13] 53%–67% in soccer players,^[14][15], 31% in sprinters,^[16] and 20%–31% in swimmers.^[17][18]

LEA may be a consequence of disordered eating behavior, the prevalence of which is increased in sports that emphasize leanness, such as aesthetic and endurance sports, as well as those that include weight classes.^[19] It can also be intentionally employed for the purpose of boosting the odds of competitive success, as body mass and body composition affect sports performance,^[20] and reducing EA can improve power to weight ratio (i.e., the amount of power an individual can produce divided by their body weight). Periods of intentional LEA are also favorable or even required in aesthetic sports like bodybuilding, in which the athlete’s appearance determines their competitive success. In a third scenario, LEA may develop unknowingly due to the athlete’s intensive exercise regimen in combination with an inadequate appetite to match daily energy demands.

When LEA is maintained over extended periods, adverse effects on health and performance can occur. These effects are characterized by the triad and relative energy deficiency in sport (RED-S) models. The triad model was conceptualized first and refers to the interrelationship between LEA, menstrual dysfunction, and compromised bone health.^[21] Building upon the triad model, RED-S was introduced in 2014 and considers the broader effects of LEA on physiological function and general well-being.^[22] It is also inclusive of male athletes. RED-S describes the effects of LEA on reproductive and bone health, as outlined in the triad model, but also impairments in additional systems (e.g., gastrointestinal, immunological, hematological), as well as psychological problems, which may precede or be caused by LEA.^[4] It’s important to note that, contrary to what some people think, the triad and RED-S are distinct and valid models that can co-exist. RED-S may be based on the triad, but it did not replace it.^[23]

The effects of low energy availability (LEA)

Adapted from Areta et al., 2021, Eur J Appl Physiol.

Although the adverse physiological effects of short-term (no more than 5 days) LEA are well documented,^[2] and it’s clear that chronic underfueling leads to adverse health and performance outcomes,^[24] the summarized study is novel and notable because it provides insight into the effect of LEA on MPS, specifically, which has not been well studied.

One other study, which was published in 2014, investigated the influence of LEA on MPS, and it found that resting myofibrillar protein synthesis was reduced by 27% in resistance-trained men and women after 5 days of a diet providing 30 kcal per kg of FFM per day (LEA) compared to 45 kcal per kg of FFM per day (OEA).^[25] Furthermore, this study found that a single bout of resistance exercise performed in the fasted state restored myofibrillar protein synthesis levels to those found in OEA at rest, and a postworkout ingestion of 15–30 grams of protein increased MPS to levels above those found in OEA at rest.

The summarized study expands on this work by using a longer intervention duration, a combined aerobic and resistance exercise program as opposed to a single bout of resistance exercise, and daily muscle protein synthesis measurements.

The results of the 2014 study suggested that resistance exercise and protein supplementation can preserve muscle mass during LEA. The results of the summarized study refute this conclusion, finding that daily rates of both myofibrillar and sarcoplasmic protein synthesis are reduced during LEA, and a high-protein diet and regular bouts of resistance exercise are unable to prevent muscle mass loss.

This finding aligns with the overall body of evidence documenting a milieu of negative physiological adaptations in response to an EA of 30 kcal per kg of FFM per day or less in women. Fundamentally, when EA is reduced, metabolic adaptations to conserve fuel occur and less energy is allocated to energetically expensive processes. The results of the summarized study suggest that muscle protein synthesis is one of these energetically expensive processes that is neglected during LEA.

As a general rule, female athletes interested in maximizing their health and performance should stay clear of prolonged exposure to an EA of 30 kcal per kg of FFM per day or less. However, it should be highlighted that this is an average figure and not everyone will experience adverse effects once this threshold is surpassed.^[3][4] For example, a study in male endurance athletes provided evidence to demonstrate the superiority of an LEA range (9–25 kcal per kg of FFM per day) over an absolute (17 kcal per kg of FFM per day) EA threshold.^[5]

Furthermore, athletes who do suffer repercussions when the general threshold for LEA is surpassed for multiple days in a row will not all experience the same severity of physiological impairment, and the impairments will not necessarily be global. For example, one study in women found that greater energy deficiency was associated with greater frequency of menstrual disturbances but not greater severity of menstrual disturbances.^[26] Also, the magnitude of reduction in levels of T3 and IGF-1 was not greater with greater energy deficiency. In addition, a study in men found that 4 days of exposure to an EA of 15 kcal per kg of FFM per day resulted in reduced levels of leptin and insulin, but not T3, testosterone, IGF-1, or ghrelin.^[27]

The researchers did not adjust for multiple comparisons, despite the inclusion of numerous outcomes, which increases the risk of false-positive results. Therefore, besides the results for myofibrillar protein synthesis, the results should be interpreted with some caution.