Muscle wasting from kidney failure—A model for catabolic conditions

Abstract

Purpose Muscle atrophy is a frequent complication of chronic kidney disease (CKD) and is associated with increased morbidity and mortality. The processes causing loss of muscle mass are also present in several catabolic conditions. Understanding the pathogenesis of CKD-induced muscle loss could lead to therapeutic interventions that prevent muscle wasting in CKD and potentially, other catabolic conditions. Major findings Insulin or IGF-1 resistance caused by CKD, acidosis, inflammation, glucocorticoids or cancer causes defects in insulin-stimulated intracellular signaling that suppresses IRS-1 activity leading to decreased phosphorylation of Akt (p-Akt). A low p-Akt activates caspase-3 which provides muscle proteins substrates of the ubiquitin-proteasome system (UPS). A low p-Akt also leads to decreased phosphorylation of forkhead transcription factors which enter the nucleus to stimulate the expression of atrogin-1/MAFbx and MuRF1, E3 ubiquitin ligases that can be associated with proteolysis of muscle cells by the UPS. Caspase-3 also stimulates proteasome-dependent proteolysis in muscle. Summary in CKD, diabetes, inflammatory conditions or in response to acidosis or excess glucocorticoids, insulin resistance develops, initiating reduced IRS-1/PI3K/Akt signaling. In CKD, this reduces p-Akt which stimulates muscle proteolysis by activating caspase-3 and the UPS. Second, caspase-3 cleaves actomyosin yielding substrates for the UPS and increased proteasome-mediated proteolysis. Third, p-Akt down-regulation suppresses myogenesis in CKD. Fourth, exercise in CKD stimulates insulin/IGF-1 signaling to reduce muscle atrophy. Lastly, there is evidence that microRNAs influence insulin signaling providing a potential opportunity to design therapeutic interventions.

Low-Frequency Electrical Stimulation Attenuates Muscle Atrophy in CKD—A Potential Treatment Strategy

“…Our previous studies proved that IGF-1 plays a central role in controlling the muscle wasting of CKD. 5,[24][25][26] In this study, we found that LFES upregulates local IGF-1 and thus, provides a means of increasing muscle mass and function. There are four lines of evidence supporting this conclusion.…”

BMI Trajectories as a Harbinger of Pre-Diabetes or Underdiagnosed Diabetes: an 18-Year Retrospective Cohort Study in Taiwan

“…4 Second, a reduction in BMI may be the result of other physiological changes during the pre-diabetes stage, 2 9 such as the beta-cell dysfunction and insulin resistance that prevent blood glucose utilization by cells and promote gluconeogenesis through muscle proteolysis. 30 The differences in BMI and development of diabetes in Asian populations have received a significant growth in interest recently. A number of studies have thus discussed the BMI cutoff points needed to identify at-risk Asian-Americans for type 2 diabetes screening and pointed out the urgent need to increase early detection.…”

Association of Reduced eGFR and Albuminuria with Serious Fall Injuries among Older Adults

“…It is also possible that microvascular disease directly impairs muscle metabolism or affects physical performance, leading to a higher risk for falls (21,22). Inflammation may also play a role in loss of muscle mass in CKD through the insulin resistance and stimulation of muscle proteolysis (23).…”