Ghrelin treatment improves physical decline in sarcopenia model mice through muscular enhancement and mitochondrial activation

Abstract

Chronic kidney disease (CKD) impairs physical performance in humans, which leads to a risk of all-cause mortality. In our previous study, we demonstrated that a reduction in muscle mitochondria rather than muscle mass was a major cause of physical decline in 5/6 nephrectomized CKD model mice. Because ghrelin administration has been reported to enhance oxygen utilization in skeletal muscle, we examined the usefulness of ghrelin for a recovery of physical decline in 5/6 nephrectomized C57Bl/6 mice, focusing on the epigenetic modification of peroxisome proliferator activated receptor gamma coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis. The mice were intraperitoneally administered acylated ghrelin (0.1 nmol/gBW; three times per week) for a month. Muscle strength and exercise endurance were measured by using a dynamometer and treadmill, respectively. Mitochondrial DNA copy number was determined by quantitative PCR. The methylation levels of the cytosine residue at 260 base pairs upstream of the translation initiation point (C-260) of PGC-1α, which has been demonstrated to decrease the expression, was evaluated by methylation-specific PCR and bisulfite genomic sequencing methods after the ghrelin administration. Ghrelin administration improved both muscle strength and exercise endurance in the mice and was associated with an increase in muscle mass and muscle mitochondrial content. Ghrelin administration decreased the methylation ratio of C-260 of PGC-1α in the skeletal muscle and increased the expression. Therefore, ghrelin administration effectively reduced the physical decline in 5/6 nephrectomized mice and was accompanied with an increased mitochondrial content through de-methylation of the promoter region of PGC-1α in the muscle.

Ghrelin mediates exercise endurance and the feeding response post-exercise

“…These effects presumably would mirror those of ghrelin demonstrated in several preclinical cachexia and muscle atrophy models and in cachectic patients with heart failure and chronic obstructive pulmonary disease [83] , [85] , [86] , [87] , [88] , [89] . Notably, in a mouse model of chronic kidney disease, ghrelin administration was shown not only to improve muscle strength and to increase skeletal muscle mitochondria-related gene expression but also to improve exercise endurance [82] , [90] . Many details regarding these latter effects of ghrelin remain unclear; interestingly, both the acyl and unacyl forms of ghrelin have been shown to mediate some of these effects [85] , [91] and GHSR expression has been detected in skeletal muscle in some but not all studies [82] , [91] , [92] , [93] , [94] .…”

New insights into the pathogenesis and treatment of sarcopenia in chronic heart failure

“…Ghrelin may be a promising therapeutic target for sarcopenia due to its positive effects on gastric motility, food intake, and growth hormone secretion. A previous study indicated that ghrelin treatment could effectively reduce the physical decline in sarcopenic mouse model through muscular enhancement and mitochondrial activation 105. Moreover, a clinical study suggested that ghrelin administration could improve left ventricular function and exercise capacity, and increase muscle strength and lean body mass in patients with CHF 106.…”

Sarcopenia in Chronic Kidney Disease: Factors, Mechanisms, and Therapeutic Interventions

“…110) Using human proximal tubular cells, a DPP-4 inhibitor showed the cell protective activity without the action of GLP-1. 111) Taking these findings into consideration, a DDP-4 inhibitor may exert cytoprotective activities not only inhibiting the degradation of GLP-1 but also via its direct action. 5.5.…”