Reduced skeletal muscle expression of mitochondrial-derived peptides humanin and MOTS-C and Nrf2 in chronic kidney disease

Abstract

Advanced chronic kidney disease (CKD) is characterized by a premature aging phenotype of multifactorial origin. Mitochondrial dysfunction is prevalent in CKD and has been proposed as a major contributor to poor muscle function. Although the mitochondria-derived peptides (MDPs) humanin and mitochondrial open reading frame of 12S rRNA-c (MOTS-c) are involved in cell survival, suppression of apoptosis, and glucose control, the implications of MDP in CKD are unknown. We investigated humanin and MOTS-c protein expression in skeletal muscle and serum levels in CKD at stage 5 (glomerular filtration rate: <15 ml/min) patients and age-matched controls with normal renal function. Whereas circulating levels of humanin were increased in CKD, local muscle expression was reduced. In contrast, MOTS-c levels were reduced in both skeletal muscle and serum in CKD. Humanin in serum correlated positively to circulating TNF levels. Reduced MDP levels in skeletal muscle were associated with lower mitochondrial density and evidence of oxidative stress. These results indicate a differential regulation of MDPs in CKD and suggest an alternative site for humanin production than skeletal muscle in the uremic milieu. MDP levels were linked to systemic inflammation and evidence of oxidative stress in the muscle, two hallmark features of premature aging and uremia.

Inflammation and Premature Ageing in Chronic Kidney Disease

“…When oxidative stress occurs, NRF2 translocates to the nucleus and activates >300 distinct genes that have an anti-oxidant response element in their promoter regions [26,116]. Mitochondrial dysfunction in CKD is associated with low NRF2 expression in human skeletal muscle [117]. NRF2 is also negatively associated with different other age-related lifestyle diseases [9] and rare progeroid syndromes [7].…”

Food as medicine: targeting the uraemic phenotype in chronic kidney disease

“…The main regulator of energy metabolism and mitochondrial biogenesis, proliferator-activated receptor coactivator-1α (PGC-1α), interacts with Nrf2 and mitochondrial transcription factor A (TFAM), which is involved in mitochondrial DNA (mtDNA) replication and transcription 169,172,173 . CKD is characterized by mitochondrial dysfunction 164,174 with downregulation of PGC-1α, dysregulation of mitochondrial biogenesis 169 , reduced skeletal muscle expression of mitochondrial-derived peptides and decreased Nrf2 expression 175 . Mitochondria are extremely susceptible to oxidative stress, and mitochondrial dysfunction leads to the establishment of a vicious cycle of overproduction of ROS 169 and activation of the inflammasome and NF-κB, which triggers further mitochondrial dysfunction, , 173 .…”

Mitochondrial Dysfunction in Kidney Disease and Uremic Sarcopenia

“…Nrf2 is important for maintaining mitochondrial function, muscle mitohormesis, and oxidative stress defense in skeletal muscle ( Coleman et al, 2018 ; Kitaoka et al, 2019 ). Moreover, Nrf2 is involved in uremic sarcopenia, which has reduced skeletal muscle mitochondrial mass and gene expression related to mitochondrial biogenesis, including Nrf2 ( Liu et al, 2019 ; Watson et al, 2020 ). Genetic Nrf2 activation in skeletal muscle improves endurance capacity and increased oxygen consumption without altering mtDNA content ( Uruno et al, 2016 ).…”