Human Skeletal Muscle Disuse Atrophy: Effects on Muscle Protein Synthesis, Breakdown, and Insulin Resistance-A Qualitative Review

Supreeth S Rudrappa, Daniel J Wilkinson, Paul L Greenhaff, Kenneth Smith, Iskandar Idris, Philip J Atherton, Supreeth S Rudrappa, Daniel J Wilkinson, Paul L Greenhaff, Kenneth Smith, Iskandar Idris, Philip J Atherton

Abstract

The ever increasing burden of an aging population and pandemic of metabolic syndrome worldwide demands further understanding of the modifiable risk factors in reducing disability and morbidity associated with these conditions. Disuse skeletal muscle atrophy (sometimes referred to as "simple" atrophy) and insulin resistance are "non-pathological" events resulting from sedentary behavior and periods of enforced immobilization e.g., due to fractures or elective orthopedic surgery. Yet, the processes and drivers regulating disuse atrophy and insulin resistance and the associated molecular events remain unclear-especially in humans. The aim of this review is to present current knowledge of relationships between muscle protein turnover, insulin resistance and muscle atrophy during disuse, principally in humans. Immobilization lowers fasted state muscle protein synthesis (MPS) and induces fed-state "anabolic resistance." While a lack of dynamic measurements of muscle protein breakdown (MPB) precludes defining a definitive role for MPB in disuse atrophy, some proteolytic "marker" studies (e.g., MPB genes) suggest a potential early elevation. Immobilization also induces muscle insulin resistance (IR). Moreover, the trajectory of muscle atrophy appears to be accelerated in persistent IR states (e.g., Type II diabetes), suggesting IR may contribute to muscle disuse atrophy under these conditions. Nonetheless, the role of differences in insulin sensitivity across distinct muscle groups and its effects on rates of atrophy remains unclear. Multifaceted time-course studies into the collective role of insulin resistance and muscle protein turnover in the setting of disuse muscle atrophy, in humans, are needed to facilitate the development of appropriate countermeasures and efficacious rehabilitation protocols.

Keywords: diabetes; disuse; immobilization; protein metabolism; skeletal muscle.

Figures

Figure 1
Figure 1
Diagrammatic representation of the main mechanisms involved in disuse skeletal muscle atrophy in humans: Immobilization/disuse reduces both postabsorptive and post prandial muscle protein synthesis (MPS) via the mammalian target of rapamycin (mTORC1) and Akt signaling. The role of MPS, muscle protein breakdown (MPB) and insulin resistance (IR) in simple disuse atrophy remain poorly defined in humans. So the role of insulin resistance and MPB in the setting of disuse atrophy needs further evaluation. Inflammation probably leads to IR. Recently, reactive oxygen species (ROS) has been implicated in development of muscle atrophy in disuse setting, but the mechanism in human remains putative. Solid arrow shows positive association and broken arrow shows putative association. See text for more details.
Figure 2
Figure 2
Diagrammatic representation of the overlap between insulin signaling pathway, reactive oxygen species (ROS), inflammatory cytokine such as NF-κB and ubiquitin-proteasome system in insulin resistant (IR) states particularly diabetes: In IR state, PI3K activity is decreased, leading to decreased activity of Akt, which in turn release the inhibition of FOXO and caspase-3 resulting in elevation of muscle ring finger-1 (MuRF-1) and muscle atrophy F-box (MAFbx/atrogin-1) finally leading to increased proteolytic activity. Also, ROS and low grade inflammation via NF-κB pathway lead to muscle atrophy. See text for more details.

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