Sarcopenia and cachexia: the adaptations of negative regulators of skeletal muscle mass

Abstract

Recent advances in our understanding of the biology of muscle, and how anabolic and catabolic stimuli interact to control muscle mass and function, have led to new interest in the pharmacological treatment of muscle wasting. Loss of muscle occurs as a consequence of several chronic diseases (cachexia) as well as normal aging (sarcopenia). Although many negative regulators [Atrogin-1, muscle ring finger-1, nuclear factor-kappaB (NF-κB), myostatin, etc.] have been proposed to enhance protein degradation during both sarcopenia and cachexia, the adaptation of mediators markedly differs among these conditions. Sarcopenic and cachectic muscles have been demonstrated to be abundant in myostatin- and apoptosis-linked molecules. The ubiquitin-proteasome system (UPS) is activated during many different types of cachexia (cancer cachexia, cardiac heart failure, chronic obstructive pulmonary disease), but not many mediators of the UPS change during sarcopenia. NF-κB signaling is activated in cachectic, but not in sarcopenic, muscle. Some studies have indicated a change of autophagic signaling during both sarcopenia and cachexia, but the adaptation remains to be elucidated. This review provides an overview of the adaptive changes in negative regulators of muscle mass in both sarcopenia and cachexia.

Fig. 1

Myostatin signals through the activin receptor IIB (Actr2b) ALK4/5 heterodimer activate Smad2/3 with the consequent nuclear translocation of Smad4 and blocking of MyoD transactivation in an autoregulatory feedback loop. In both sarcopenic and cachectic muscles, abundant activated Smad2/3 inhibit protein synthesis, probably due to blocking of the functional role of Akt. In sarcopenic muscle, Akt can block the nuclear translocation of FOXO to inhibit the expression of Atrogin-1. In contrast, the impaired regulation of FOXO by Akt results in the abundant expression of Atrogin-1 and the consequent protein degradation in cachectic muscle. Although the blood and muscle levels of TNF-α were increased in both muscle wasting, the elevation of NF-κB occurs in cachectic but not sarcopenic muscles. Both muscle wasting include the enhancement of apoptosis signaling. IGF-I insulin-like growth factor I, IGF-IR IGF-I receptor, PI3-K phosphatidylinositol 3-kinase, TORC1 component of TOR signaling complex 1, Rheb Ras homolog enriched in brain, mTOR mammalian target of rapamycin, eIF4E eukaryotic initiation factor 4E, FOXO forkhead box O, IKK inhibitor of κB kinase, NF-κB nuclear factor of kappa-B, MuRF1 muscle ring finger protein 1, TNF tumor necrosis factor