Sarcopenia: Tilting the Balance of Protein Homeostasis

Abstract

Sarcopenia, defined as age‐associated decline of muscle mass and function, is a risk factor for mortality and disability, and comorbid with several chronic diseases such as type II diabetes and cardiovascular diseases. Clinical trials showed that nutritional supplements had positive effects on muscle mass, but not on muscle function and strength, demonstrating our limited understanding of the molecular events involved in the ageing muscle. Protein homeostasis, the equilibrium between protein synthesis and degradation, is proposed as the major mechanism underlying the development of sarcopenia. As the key central regulator of protein homeostasis, the mammalian target of rapamycin (mTOR) is proposed to be essential for muscle hypertrophy. Paradoxically, sustained activation of mTOR complex 1 (mTORC1) is associated with a loss of sensitivity to extracellular signaling in the elderly. It is not understood why sustained mTORC1 activity, which should induce muscle hypertrophy, instead results in muscle atrophy. Here, recent findings on the implications of disrupting protein homeostasis on muscle physiology and sarcopenia development in the context of mTOR/protein kinase B (AKT) signaling are reviewed. Understanding the role of these molecular mechanisms during the ageing process will contribute towards the development of targeted therapies that will improve protein metabolism and reduce sarcopenia.

Experimental Models of Sarcopenia: Bridging Molecular Mechanism and Therapeutic Strategy

“…Skeletal muscle atrophy results from protein turnover under disrupted protein homeostasis conditions, i.e., abnormality in protein synthesis or protein degradation, which is controlled by multiple signaling pathways [60]. A major regulatory pathway of intracellular protein homeostasis is the Akt/mammalian target of the rapamycin (mTOR) pathway that has become an attractive target for sarcopenia research [61,62]. Indeed, activation of Akt signaling increases protein synthesis through activation of mTOR complex 1 (mTORC1)-mediated phosphorylation of S6 kinase (S6K) and inhibition of 4E-BP1.…”

“…Indeed, activation of Akt signaling increases protein synthesis through activation of mTOR complex 1 (mTORC1)-mediated phosphorylation of S6 kinase (S6K) and inhibition of 4E-BP1. On the other hand, Akt can limit abnormal protein degradation in skeletal muscles and atrophy via phosphorylation of the transcription factor forkhead box O (FoxO) [62]. Although Akt/mTOR signaling pathways in muscles and other tissues are well understood, the implication of Akt/mTOR signaling during skeletal muscle aging is still under debate.…”

“…The UPS tightly regulates protein homeostasis via conjugation of multiple ubiquitin moieties (ubiquitination) mediated by ubiquitin ligases and degradation of ubiquitin-tagged proteins mediated by the proteasome complex. In skeletal muscles, the major muscle-specific E3 ubiquitin ligases include muscle atrophy F-box (MAFbx)/atrogin-1 and muscle ring finger 1 (MuRF1) [62,65]. It has been hypothesized that increased protein degradation via these types of machinery contributes to sarcopenia.…”

“…The use of genetically engineered mice in sarcopenia research has progressively increased over the past years and has contributed to the knowledge of this geriatric disease. Decreased muscle protein synthesis and increased muscle protein degradation have been proposed to underlie the pathogenesis of sarcopenia [62]. Several studies on skeletal muscle atrophy have used mice with genetic modifications.…”

The TOR Pathway at the Neuromuscular Junction: More Than a Metabolic Player?

“…One of the underlying drivers of the aging process is a change in proteostasis, the balance between protein synthesis and protein degradation ( Tan et al, 2019 ). Alterations in proteostasis have also been implicated in neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS) ( Ferri and Coccurello, 2017 ).…”