Dietary energy and protein intake are nutritional determinants of skeletal muscle mass. Maintenance of skeletal muscle mass is generally achieved by consuming sufficient energy to meet energy demand and protein at levels consistent with the U.S. recommended dietary allowance (RDA; 0.8 g/kg per day) (1). However, during periods of increased energy demand, protein requirements to sustain protein retention and the maintenance of skeletal muscle mass are increased above the RDA. It is currently recommended that physically active individuals (e.g., aerobic and resistance exercise type athletes) consume 1.2 to 1.7 g protein/kg per day (2–4). Likewise, it is recommended that military personnel undergoing metabolically challenging training and combat operations consume a diet providing 1.5 to 2.0 g/kg per day of protein to facilitate the repair of damaged proteins, synthesis of new muscle proteins, and maintenance of muscle mass (5). Therefore, it is not surprising that high‐protein diets have increased in popularity among physically active, normal‐weight adults (3).

In general, overweight and obese individuals adhering to a sustained, moderate energy‐deficient diet lose fat and lean body mass (LBM), which approximates 75% fat mass and 25% LBM (6). However, decrements in LBM can be more severe in normal‐weight individuals, such as athletes and military personnel, who often undergo unavoidable energy deficits of greater severity (7). The loss of LBM in active populations can lead to degraded performance and increased injury risk (8, 9). Fortunately, protein intake above the RDA is skeletal muscle protective, as studies have consistently shown that consuming protein at twice the RDA spares LBM and that this metabolic advantage is independent of body size (6, 7, 10‐12).

Although the independent effects of dietary energy and protein intake on body composition have been studied extensively, and potential energetic, endocrine, and the behavioral mechanisms to account for body composition adaptations to energy and protein manipulations have been explored (13–16), the interaction between energy status and protein intake on skeletal muscle protein turnover and associated regulatory systems remains largely unexplored (7, 17‐22). Given that muscle protein turnover, especially muscle protein synthesis (MPS), is a primary regulator of skeletal muscle mass (23) and that the stimulatory effects of dietary protein on MPS are well documented (24–26), the lack of studies in this area of nutritional science is intriguing. Recent studies from our group (7, 20) and others (17) have provided consistent data demonstrating interactive effects of energy and protein on muscle protein turnover. This article highlights the molecular and nutritional regulation of skeletal muscle mass with emphasis given to recent studies establishing a mechanistic link between energy and protein intake on muscle protein turnover, and it proposes new research to identify appropriate nutritional strategies to mitigate skeletal muscle loss during energy deficit.

Molecular regulation of human skeletal muscle protein turnover Skeletal muscle protein turnover is a dynamic process that encompasses the synthesis of new proteins and breakdown of existing proteins. The rate of muscle protein turnover is dependent on amino acid availability and endogenous protein breakdown (26, 27). Cycling of amino acids between MPS and muscle protein breakdown (MPB) is critical for growth, maintenance, and repair of body tissues, which facilitate adaptation and recovery from physical stressors (25). Dysregulation of muscle protein turnover can contribute to the progression of LBM loss (28–30). Skeletal muscle protein turnover is regulated by intracellular anabolic (23) and proteolytic systems (31). Cellular regulation of MPS is mediated by the mechanistic target of rapamycin complex 1 (mTORC1) (32, 33). Energy status and protein intake modulate mTORC1 signaling, mRNA translation, and ultimately MPS (32, 33). Specifically, energy deprivation up‐regulates AMP‐activated protein kinase, thereby diminishing mTORC1 signaling and MPS (34). However, consuming protein either alone or in a mixed‐macronutrient meal promotes a robust increase in MPS (35, 36). The anabolic response to protein ingestion occurs as a result of postprandial increases in extracellular amino acid availability (26, 37), insulin secretion (38), and muscle intracellular amino acid transporter expression (39). This sequence leads to increased muscle intracellular amino acid levels, which in turn stimulates mTORC1 and downstream activation of p70 S6 kinase and inactivation of the repressor of mRNA translation, eukaryotic initiation factor 4E‐binding protein (40–44). Dietary protein sources that contain high levels of the branched‐chain amino acid leucine are particularly effective at increasing MPS. The effectiveness of leucine seems to stem from interactions with the Rag subfamily of Rag small GTPases and subsequent lysosomal translocation of mTORC1 (43, 44). MPB provides amino acid precursors to sustain MPS and support hepatic gluconeogenesis (45–47). Four proteolytic systems contribute to MPB, including the ubiquitin proteasome system (UPS), autophagy‐lysosomal, calcium‐dependent calpains, and the cysteine protease caspase enzymes (48, 49). The UPS is the primary mechanism by which skeletal muscle is degraded (31, 50). The UPS is a highly regulated, irreversible process that involves energy‐dependent ubiquitylation of muscle proteins through a discrete series of reactions catalyzed by 3 distinct enzyme complexes. This process begins with calpain and caspase 3‐dependent myofibril cleavage, resulting in smaller, more accessible actomyosin fragments (51, 52). These fragments are then marked for degradation by covalent binding of multiple ubiquitin molecules catalyzed by the enzymes E1 (ATP‐dependent ubiquitin‐activating enzyme), E2 (ubiquitin‐conjugating enzyme), and E3 (ubiquitin‐ligating enzymes). The polyubiquitin chain is recognized by the 26S proteasome, a large multisubunit proteolytic complex consisting of a central catalytic core (20S proteasome) and 2 terminal regulator complexes (19S complexes). The 19S regulator complex plays a central role in the recognition and unfolding of the ubiquitylated proteins and guides them to the 20S catalytic core for subsequent protein hydrolysis. Activity and expression of the UPS is up‐regulated under conditions of metabolic stress and is thought to be regulated in part through the insulin‐mediated mTORC1 intracellular signaling pathway (53).