Hypoxia-inducible factor-prolyl hydroxylase inhibitor ameliorates myopathy in a mouse model of chronic kidney disease

Abstract

Muscle wasting and diminished physical performance contribute to the morbidity and mortality of chronic kidney disease (CKD), for which no curative therapy exists. Accumulating evidence indicates that impaired angiogenesis occurs in the muscles of CKD models. Therefore, proangiogenesis therapy is considered a potentially effective strategy for limiting CKD-associated myopathy. Hypoxia-inducible factor (HIF)-prolyl hydroxylase inhibitor (HIF-PHI) stabilizes HIF and enhances muscle angiogenesis during acute ischemia; however, little evidence was available from CKD models. Here, we assessed whether pharmacological activation of HIF by MK-8617 (MK), a novel orally active HIF-PHI, improves CKD-associated myopathy. Mice were divided into sham or CKD groups, and CKD mice were subdivided into CKD + vehicle or MK treatment groups (1.5, 5, or 12.5 mg/kg for 12 wk). In CKD mice, skeletal muscle mass, mitochondrial amount, and exercise capacity decreased compared with sham mice. Compared with the CKD + vehicle group, low (1.5 mg/kg) and medium (5 mg/kg) doses of MK, but not the high dose (12.5 mg/kg), significantly restored these changes and was accompanied by incremental increases in HIF-1α. Furthermore, increased capillary density and area were observed in a MK dose-dependent manner, which is likely related to an improved VEGF response in the skeletal muscle of CKD mice. In addition, macrophage and proinflammatory cytokines, including monocyte chemoattractant protein 1, TNF-α, and IL-6, significantly increased in the high-dose MK group. These results indicate that HIF-PHI provides a potential therapeutic strategy to improve CKD-associated myopathy.

Mitochondrial Dysfunction in Kidney Disease and Uremic Sarcopenia

“…HIF-PH inhibitors have also been reported to reduce the levels of ROS with glycolytic metabolic shift and increase cell viability in renal proximal tubule cells ( Ito et al, 2020 ) and neuronal cells with glutamate-induced oxytosis ( Neitemeier et al, 2016 ). HIF-PH inhibitor MK-8617 ameliorates myopathy in 5/6 nephrectomy CKD mice and corrects abnormalities in the mitochondrial number and size in skeletal muscle ( Qian et al, 2019 ). Future HIF-PH inhibitors as novel HIF stabilizers may relieve uremic sarcopenia, but they require further investigation.…”

Uremic Sarcopenia: Clinical Evidence and Basic Experimental Approach

“…Regarding skeletal muscle manifestation, several groups observed skeletal muscle atrophy presenting with not only bodyweight reduction, but also with a decrease of the total mass and CSA of the muscle compared with sham mice [ 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 ]. Treadmill running distance [ 93 , 113 ] and hanging time on the grid with four limbs [ 102 ] were shortened and grip strength had also deteriorated [ 89 ], while some parameters indicating lowered physical activity were not consistently affected [ 94 , 113 ]. In addition, mouse ambulation, as indicated by overnight cage activity and swimming velocity, was reduced [ 90 ].…”

“…In addition, mouse ambulation, as indicated by overnight cage activity and swimming velocity, was reduced [ 90 ]. Histologically, skeletal fibrosis was noted [ 95 ] and the number of CD31-positive capillaries was decreased [ 102 ]. In terms of molecular biology, elevation of myostatin, atrogin-1, muscle RING-finger protein-1 (MuRF-1), and an increase in an inflammatory signal such as IL-6, and acceleration of muscle protein degradation are also noted [ 91 , 94 , 96 , 99 ], although alteration of muscular protein synthesis varies between reports.…”

“…Interestingly, a decrease in skeletal muscle mass, mitochondrial amount, and exercise capacity in subtotal nephrectomized mice were restored by a 12 week treatment with an orally active HIF-PH inhibitor, MK-8617 (1.5 to 12.5 mg/kg). Increased capillary density in skeletal muscle is ancillary to muscle function improvement, which may be caused by the upregulation of HIF-downstream VEGF expression [ 102 ]. Our laboratory also focused on the pharmacological effect of HIF-PH inhibitor on skeletal myocytes and tissue and also clarified that the pharmacological treatment enhanced glycolysis and suppressed the tricarboxylic acid (TCA) cycle, thus mimicking the Walberg effect in tumors (Takemura, Nishi, unpublished).…”

If it’s not one thing, HIF’s another: immunoregulation by hypoxia inducible factors in disease

“…Macrophage behaviours during wound repair can be improved using HIF‐directed therapies. In a mouse model of chronic kidney disease, the PHD inhibitor MK‐8617 increased the infiltration of macrophages into damaged muscle, improving muscle repair and reducing muscle atrophy [29]. Additionally, treatment of HIF‐α inhibitor YC‐1, in a mouse injury model, decreased numbers of pro‐inflammatory macrophages in scar tissue and reduced levels of pro‐inflammatory cytokines in vivo [30].…”