Improvement of Physical Decline Through Combined Effects of Muscle Enhancement and Mitochondrial Activation by a Gastric Hormone Ghrelin in Male 5/6Nx CKD Model Mice

Abstract

Because a physical decline correlates with an increased risk of a wide range of disease and morbidity, an improvement of physical performance is expected to bring significant clinical benefits. The primary cause of physical decline in 5/6 nephrectomized (5/6Nx) chronic kidney disease model mice has been regarded as a decrease in muscle mass; however, our recent study showed that a decrease in muscle mitochondria plays a critical role. In the present study, we examined the effects of a gastric hormone ghrelin, which has been reported to promote muscle mitochondrial oxidation, on the physical decline in the chronic kidney disease model mice, focusing on the epigenetic modulations of a mitochondrial activator gene, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). Ghrelin treatment improved a decline in exercise endurance of 5/6Nx mice, associated with an increase in both of the muscle mass and mitochondrial amount. The expression level of PGC-1α was decreased in the skeletal muscle of 5/6Nx mice, which was associated with an increase in the methylation ratio of the cytosine residue at 260 base pairs upstream of the initiation point. Conversely, ghrelin treatment de-methylated the cytosine residue and increased the expression of PGC-1α. A representative muscle anabolic factor, IGF-1, did not affect the expression of PGC-1α and muscle mitochondrial amount, although it increased muscle mass. As a result, IGF-1 treatment in 5/6Nx mice did not increase the decreased exercise endurance as effectively as ghrelin treatment did. These findings indicate an advantage of ghrelin treatment for a recovery of physical decline.

Growth hormone secretagogues hexarelin and JMV2894 protect skeletal muscle from mitochondrial damages in a rat model of cisplatin-induced cachexia

“…Moreover, ghrelin could have also an epigenetic effect as Tamaki et al . 61 reported a demethylation of the cytosine residue upstream of the transcription initiation site of PGC-1α. It would be interesting to investigate the consequences of these effects and if these are extended to hexarelin and JMV2894.…”

“…Hexarelin and JMV2894 might stimulate growth hormone (GH) release and this may activate PGC-1α through the IGF1-AKT-mTOR-YY1 pathway. Accordingly, IGF-1 has been proposed as countermeasure against muscle impairment in disuse 61 . PGC-1α may then activate mitochondrial biogenesis, mitochondrial antioxidants and inhibit FoxO3a activity.…”

Clinical practice guideline for renal rehabilitation: systematic reviews and recommendations of exercise therapies in patients with kidney diseases

“…CKD patients are likely to develop a condition called protein-energy wasting (PEW), in which body protein mass is reduced by protein catabolism, etc. Also, the endurance capacity is reduced due to mitochondrial dysfunction [11,12]. Such abnormal muscle metabolism associated with CKD may be improved by renal rehabilitation.…”

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

“…These renal toxicity and cardiovascular damage were stimulated by enhancing oxidative stress and inflammation. [49][50][51][52][53][54] In addition, A high-protein diet not only exacerbates impaired renal function but also reduces exercise endurance in CKD mice, 55) which is accompanied by the increased uremic toxins production. 56) These evidences hypothesize that protein-bound uremic toxins play an essential role in muscle atrophy and reduced endurance.…”