Amino Acid Sensing in Skeletal Muscle

Abstract

Aging impairs skeletal muscle protein synthesis, leading to muscle weakness and atrophy. However, the underlying molecular mechanisms remain poorly understood. Here, we review evidence that mammalian/mechanistic target of rapamycin complex 1 (mTORC1)-mediated and activating transcription factor 4 (ATF4)-mediated amino acid (AA) sensing pathways, triggered by impaired AA delivery to aged skeletal muscle, may play important roles in skeletal muscle aging. Interventions that alleviate age-related impairments in muscle protein synthesis, strength, and/or muscle mass appear to do so by reversing age-related changes in skeletal muscle AA delivery, mTORC1 activity, and/or ATF4 activity. An improved understanding of the mechanisms and roles of AA sensing pathways in skeletal muscle may lead to evidence-based strategies to attenuate sarcopenia.

Keywords: activating transcription factor 4; general control nonderepressible 2; leucine; mammalian/mechanistic target of rapamycin complex 1; tomatidine; ursolic acid.

FIGURE I. Proposed amino acid sensing mechanisms in skeletal muscle fibers

A hypothetical muscle fiber (adapted from reference 45) is shown that highlighting the recently identified AA sensing apparatus for leucine and arginine signaling to mTORC1. However, it is currently unknown whether leucine and arginine sensing in skeletal muscle cells is identical to what has been identified in kidney cells.

Figure 1. Increased AA delivery to muscle enhances AA sensing and activates protein synthesis

We propose three main mechanisms that regulate AA sensing within muscle cells. 1) Vascular endothelial function is important for enhancing nutrient and hormone delivery to muscle tissue via vasodilation. 2) AA transport from the blood, across the endothelial cell, through the interstitial space, and eventually into muscle cells is dependent upon functional AA transporters. 3) AA sensing via activation of mTORC1 signaling and inhibition of ATF4 are important for fully activating muscle protein synthesis in response to AA sufficiency.

Figure 2. Impact of ATF4, ursolic acid, and tomatidine on skeletal muscle during aging

The schematic shows a model of the effects of ATF4, ursolic acid, and tomatidine in skeletal muscle and with aging. ATF4 is required for the loss of skeletal muscle strength, quality and mass during aging [49]. Ursolic acid and tomatidine are natural compounds that blunt ATF4 activity in aged skeletal muscle, leading to reduced weakness and atrophy in aged skeletal muscle [49].