What is the biochemical basis of anabolic resistance in skeletal muscle?
What are the relative contributions of endothelial dysfunction and physical inactivity in the development
Aging reduces skeletal muscle strength and muscle quality (i.e., strength per unit muscle mass) and ultimately causes age-related skeletal muscle atrophy, also known as sarcopenia. The early stages of skeletal muscle aging are primarily marked by reduced strength, which becomes apparent around the age of 40, and can progressively impair normal activities and quality of life. The late stage of skeletal muscle aging, sarcopenia, has serious health consequences, including falls, immobility, loss of independent living, and increased mortality [1]. The cellular and molecular mechanisms of skeletal muscle aging are complex, just beginning to be revealed, and still poorly understood. Here, we review current evidence linking skeletal muscle aging to amino acid (AA) sensing mechanisms within skeletal muscle fibers.
Muscle mass is ultimately controlled by the cellular processes of protein synthesis and breakdown (i.e., protein turnover). During conditions of muscle growth or hypertrophy, the rate of protein synthesis exceeds the rate of protein breakdown (i.e., muscle protein anabolism). However, muscle catabolism occurs when the rate of protein breakdown exceeds the rate of protein synthesis. In all types of skeletal muscle atrophy, including sarcopenia, the normal balance between protein synthesis and
As mentioned in the previous section, AA delivery to muscle is impaired with aging. Vascular tone in humans is determined via a balance between local vasoconstrictors and vasodilators produced by the endothelium [31]. Insulin stimulates NO production by activating endothelial NOS, which results in vasodilation, increased muscle perfusion, and capillary recruitment [25]. It is also well known that aging is associated with reduced endothelial-derived vasodilation, which appears to be due to an
Because AAs are required for virtually every cellular process, impairments in skeletal muscle AA delivery could theoretically cause a catastrophic reduction in AA levels within skeletal muscle fibers. Fortunately, however, all mammalian cell types, including muscle fibers, possess evolutionarily ancient regulatory mechanisms that sense small changes in intracellular AA levels (see Figure I in Box 1). When intracellular AA levels begin to fall, these AA sensing pathways reduce protein synthesis
Endothelial dysfunction is an attribute of aging. One bout of aerobic exercise can temporarily restore endothelial dysfunction, and aerobic exercise training can significantly improve endothelial function, in older adults [53]. In the aforementioned studies, acute aerobic exercise is effective at improving the anabolic action of insulin and AAs in aged human skeletal muscle [33], whereas bed rest in older adults reduces the anabolic action of AAs in muscle [38]. In addition, one study found
The underlying mechanisms of skeletal muscle aging are still poorly understood, however, reduced AA delivery to skeletal muscle and activation of mechanisms that sense low levels of AAs within skeletal muscle appear to play important roles. Furthermore, recent advances in aging and muscle biology research emphasize the need for a better understanding of the biochemical basis of anabolic resistance, including a more complete definition of the roles and relationships of aging, physical activity,
C.M.A. and S.M.E. are inventors on patent applications related to ursolic acid and tomatidine, which have been filed by the University of Iowa Research Foundation and licensed to Emmyon, Inc. C.M.A. is a founder and officer of Emmyon, Inc. SME is an employee of Emmyon, Inc. C.M.A. and S.M.E. hold equity in Emmyon, Inc. What is the biochemical basis of anabolic resistance in skeletal muscle? What are the relative contributions of endothelial dysfunction and physical inactivity in the development
This work was supported by grants from the National Institutes of Health (R56 AG051267, P30 AG024832, R43 AG044898, R43 AR069400, and R41 AG047684), the Department of Veterans Affairs Biomedical Laboratory Research & Development Service (IBX000976A), the Department of Veterans Affairs Rehabilitation Research and Development Service (1I01RX001477), and the Fraternal Order of Eagles Diabetes Research Center at the University of Iowa.
The protective effect of TD against skeletal muscle weakness and atrophy has been investigated further to show that the muscle-promoting effect of TD implicated a reduced expression of the activating transcription factor 4 (ATF4), which is one of the regulators of age-related muscle weakness and atrophy [86]. Like the pentacyclic triterpenoid ursolic acid, TD regulates ATF4-dependent gene expression to promote muscle protein synthesis [103]. An upregulation of ATF4 can be caused by different factors, such as the tumor necrosis factor-α (TNFα), one of the most important pro-inflammatory cytokines, but this effect can be suppressed by a pretreatment with TD, as shown in a study with C2C12 myoblasts.