Role and potential mechanisms of anabolic resistance in sarcopenia

Abstract

There is pressing need to understand the aging process to better cope with its associated physical and societal costs. The age-related muscle wasting known as sarcopenia is a major contributor to the problems faced by the elderly. By hindering mobility and reducing strength, it greatly diminishes independence and quality of life. In studying the factors that contribute to the development of sarcopenia, the focus is shifting to the study of disordered muscle anabolism. The abnormal response of muscle to previously well-established anabolic stimuli is known as anabolic resistance, and may be a key factor in the development and progression of sarcopenia. Factors such as age, obesity, inflammation, and lipotoxicity contribute to anabolic resistance, and have been studied either directly or indirectly in cell systems and whole animals. Understanding the physiologic and mechanistic basis of anabolic resistance could be the key to formulating new and targeted interventions that would ease the burden currently borne by the world's aged population.

Fig. 1

Anabolic stimuli in the form of amino acids, growth factors (insulin, IGF-1), and exercise (not shown) act through the mTOR and Akt signaling pathways. mTORC1 is responsible for the phosphorylation and activation of S6K1 and phosphorylation and inactivation of 4E-BP1. It results in ribosome biogenesis, increase in translational efficiency, and heightened MPS. The energy sensor AMPK inhibits this pathway, and is active when the AMP/ATP ratio is high. Growth factor stimulates activation of the PI3K pathway as well as mTORC2; both eventually activate Akt, which can inhibit stress signaling and apoptosis through inactivation of FOXO1/O3 transcription factors. Akt also plays a role in carbohydrate metabolism. P phosphorylation, activation or inactivation; PI3K phosphoinositide 3 kinase; Akt protein kinase B; FOXO forkhead protein box O; AMPK AMP-activated kinase; 4E-BP1 eIF4E-binding protein 1; S6K1 S6 kinase 1