The ubiquitin–proteasome pathway is the most important mechanism for protein degradation in skeletal muscle cells. This system involves a series of enzymatic steps in which the degraded proteins are first targeted by an enzyme system that binds the target protein to the polypeptide ubiquitin. These ubiquitinized proteins are then transferred to the proteasome complex and degraded into short peptides and are finally recycled as free intracellular amino acids [42].

#Screening Library randurls[1|1|,|CHEM1|]# This pathway is promoted by inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), by hormones such as cortisol and angiotensin, as well as by reactive oxygen species. Increased expression of these inflammatory cytokines also appears to be common in aging in skeletal muscle. Comparison of skeletal muscle biopsies from younger and older subjects showed increased expression of genes upregulated by inflammatory factors [43]. Levels of catabolism-inducing

hormones such as cortisol have also been shown to increase with age, and cortisol is linked to increased expression of IL-6 and TNF-α. Increased TNF-α expression is also known to stimulate muscle atrophy through apoptosis. Apoptosis contributes to the loss of myonuclei in skeletal muscle cells and could theoretically result in the loss of complete fibers in sarcopenia [44]. Oxidative damage Oxidative metabolism generates reactive oxygen species (ROS), and these metabolic products are thought to accumulate over time, altering and damaging cell BGB324 supplier components, particularly mitochondria and DNA sequences [45]. Because mitochondria produce ROS, they are subject to alterations in their structure

and in their DNA. Alterations to mtDNA are known to increase with age in skeletal muscle, and the frequency of abnormal mitochondrial Rho regions is higher in those muscles which are strongly affected by sarcopenia [45–47]. The role of mitochondrial DNA alterations in age-related loss of skeletal muscle function is under intense investigation, focusing on their roles in causing skeletal muscle cell apoptosis and structural abnormalities that affect metabolic function. Structural alterations to mitochondria may affect the electron transport chain, compromising respiration. Although the loss of maximal oxygen consumption (VO2 max) with age has been primarily attributed to loss of muscle mass and reduced cardiac output, altered mitochondrial metabolism, leading to poorer muscle cell respiration, may also be involved. Intrinsic changes to skeletal muscle One potential mechanism for sarcopenia involves the loss of muscle regenerative capacity due to loss in the number and function of muscle satellite cells, which proliferate and differentiate into skeletal muscle fibers.