commentary
7.
8.
9.
associated chronic renal failure. Am J Physiol Renal Physiol 2009; 297: F410–F419. Yuan P, Xue H, Zhou L et al. Rescue of mesangial cells from high glucose-induced over-proliferation and extracellular matrix secretion by hydrogen sulfide. Nephrol Dial Transplant 2011; 26: 2119–2126. Lee HJ, Mariappan MM, Feliers D et al. Hydrogen sulfide inhibits high glucose-induced matrix protein synthesis by activating AMPactivated protein kinase in renal epithelial cells. J Biol Chem 2012; 287: 4451–4461. Triptara P, Patel NSA, Collino M et al. Generation of endogenous hydrogen sulfide by cystathionine gamma-lyase limits renal
10.
11.
12.
ischemia/reperfusion injury and dysfunction. Lab Invest 2008; 88: 1038–1048. Bos EM, Wang R, Snijder PM et al. Cystathionine gamma-lyase protects against renal ischemia/reperfusion by modulation oxidative stress. J Am Soc Nephrol 2013; 24: 759–770. Della Coletta Francescato H, Cunha FQ, Costa RS et al. Inhibition of hydrogen sulphide formation reduces cisplatin-induced renal damage. Nephrol Dial Transplant 2011; 26: 479–488. Song K, Wang F, Li Q et al. Hydrogen sulfide inhibits the renal fibrosis of obstructive nephropathy. Kidney Int 2014; 85: 1318–1329.
see basic research on page 1330
Decrease of muscle volume in chronic kidney disease: the role of mitochondria in skeletal muscle Hideki Yokoi1 and Motoko Yanagita1 Reduced muscle volume and impaired exercise endurance are welldocumented phenomena in chronic kidney disease, and the relevant molecular mechanisms have been gradually unveiled. Tamaki et al. demonstrate a reduction of mitochondria content in skeletal muscles as a novel mechanism of reduced exercise endurance in renal insufficiency. In addition, they show that a high-protein diet reduces exercise endurance through an inhibition of muscle pyruvate dehydrogenase. Kidney International (2014) 85, 1258–1260. doi:10.1038/ki.2013.539
Physical activity plays a major role in patient mortality and morbidity; however, exercise performance and endurance are known to decline in patients with chronic kidney disease (CKD).1 These individuals are at a higher risk for cardiovascular diseases because of this reduced exercise performance and endurance. Previous studies have shown that increased levels of inflammatory cytokines are associated with decreased mobility and subsequent development of disabilities due to a deterioration of muscle strength. To 1
Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan Correspondence: Motoko Yanagita, Department of Nephrology, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. E-mail: [email protected] 1258
date, efforts have been made to reveal the molecular mechanisms involved in the association between decreased muscle volume and CKD. Muscle mass reduction is considered to be due, at least in part, to an imbalance in protein synthesis and degradation via the ubiquitin–proteasome system,2 acid– base imbalance,3 insulin resistance,3 inflammation, and decreased exercise ability. The insulin-like growth factor I (IGF-I)/insulin receptor substrate 1 (IRS-1)/phosphatidylinositol 3-kinase (PI3K)/Akt pathway is considered a key pathway in protein degradation.2,3 Activation of the PI3K/Akt pathway supports multiple mechanisms for cellular proliferation, apoptosis inhibition, cellular migration, and cytoskeletal organization. The Akt protein family of serine/threonine kinases is
central to the regulation of and adaptation to many cellular stress-induced processes. Decreased Akt phosphorylation activates the ubiquitin pathway, which promotes muscle volume reduction through caspase-3 activation. In CKD, the E3 ubiquitin-conjugating enzyme is activated to promote protein degradation. Two ubiquitin ligases, atrogin-1/muscle atrophin F-box (MAFbx) and muscle ring finger 1 (MuRF1), are specifically expressed in muscle tissues and are known to correlate with muscle atrophy. Furthermore, caspase-3 activation gives rise to expression of a 14-kDa actin fragment, a potential marker of muscle mass reduction (Figure 1). Mitochondria are highly differentiated subcellular organelles that produce adenosine triphosphate (ATP) via oxidative phosphorylation.4 They are essential organelles that maintain the muscle mobility necessary for physical activity. Exercise endurance is closely associated with mitochondria concentrations in muscle tissues and electron transport complex activity. ATP is also produced by glycolysis and the tricarboxylic acid cycle. Pyruvate dehydrogenase regulates the entry of glycolytic products into the tricarboxylic acid cycle via oxidative decarboxylation of pyruvate to acetylcoenzyme A in the mitochondria of mammalian cells. Several studies have reported a decrease in pyruvate dehydrogenase activity in rat muscles in response to fasting and in diabetic models.5 In contrast, exercise- or contraction-induced increases in pyruvate dehydrogenase activity have been demonstrated in both human and rat models.5 Pyruvate dehydrogenase is considered to be a key enzyme responsible for switching from anaerobic to aerobic carbohydrate metabolism. AMP-activated protein kinase (AMPK) is a key regulator that inactivates acetyl-coenzyme A carboxylase, thereby promoting fatty acid oxidation and mitochondrial biogenesis.6 Administration of 5-aminoimidazole-4carboxamide ribonucleoside (AICAR), an AMPK activator, to rats results in increased skeletal muscle citrate synthase and cytochrome c activity, suggesting an increased amount of mitochondria. One Kidney International (2014) 85
commentary
Renal insufficiency Uremic toxin
Oxidative stress pAMPK
Renal insufficiency + high-protein diet
Inflammation
PGC-1α
PDH
? Mitochondrial amount Cleaved caspase-3 At early phase
Exercise endurance Cleaved caspase-3
At late phase
Muscle volume
Muscle power
Muscle atrophy
Figure 1 | Decrease of muscle volume in renal insufficiency. In subtotally nephrectomized mice, inflammatory cytokines and oxidative stress were elevated in the plasma, which reduced peroxisome proliferator-activated receptor-g coactivator-1a (PGC-1a) and phosphorylated AMP-activated protein kinase (AMPK). Young mice with renal insufficiency exhibited decreased mitochondrial content and reduced exercise endurance but maintained muscle volume and power. In contrast, aged mice with 5/6 nephrectomy showed reduced muscle volume and power as well as decreased mitochondrial amount and muscle endurance. Subtotally nephrectomized mice fed a high-protein diet exhibited a reduction of pyruvate dehydrogenase (PDH) activity in skeletal muscle, leading to a reduction in mitochondrial amount and exercise endurance.
of the mechanisms by which AMPK regulates the expression of mitochondrial enzymes involves regulating various transcription factors, including peroxisome proliferator-activated receptor-g coactivator-1a (PGC-1a), which is considered to be the vital regulator of mitochondrial content in mammalian tissues (Figure 1). PGC-1a was originally shown to induce mitochondrial biogenesis in cultured myocytes. Furthermore, PGC-1a overexpression in skeletal muscles increases type I fiber activity and subsequent resistance to muscle fatigue. In addition to the above-mentioned molecular mechanisms, Tamaki et al.7 (this issue) clarify a new mechanism in the reduction of exercise endurance and muscle volume in mice with renal insufficiency by focusing on the decrease of muscle mitochondria. Although the C57BL/6 strain is well known to be resistant against renal insufficiency after 5/6 nephrectomy,8 the authors successfully developed mice with renal insufficiency in this study. They investigated age differences in muscle volume and found that young mice with 5/6 nephrectomy showed a decrease in mitochondria content in type I (slow oxidative) and IIa (fast oxidative glycolytic) skeletal muscles and a decrease in running distance, despite the preservation of muscle volume and Kidney International (2014) 85
strength. Type I fibers are characterized by increased mitochondria content and oxidative state. Young mice also showed an increase in 14-kDa actin fragment content and caspase-3 expression, indicating increased protein degradation in skeletal muscle. Furthermore, a reduction of PGC-1a and phosphorylated AMPK was also found in these mice, indicating decreased mitochondria content. In contrast, aged mice lost muscle volume and power, in addition to the reduction in skeletal muscle mitochondria content. The underlying mechanism by which aged mice lost muscle volume might be dependent on prolonged activation of the proteasome pathway. The authors further demonstrated that a high-protein diet increased muscle mass and strength but reduced muscle endurance as characterized by reduced mitochondria content and AMPK activation. A high-protein diet elicits the accumulation of lactate and the reduction of pyruvate dehydrogenase, leading to physical performance impairment that is probably due to oxidative stress. An earlier report also showed the deteriorative effect on body physique of a high-protein diet in renal failure: rats with chronic renal failure fed a highprotein diet exhibited reduced body weight and length compared with those
fed a normal-protein diet, because of anorexia, uremia, and acidosis.9 Lastly, the authors successfully demonstrated that the pyruvate dehydrogenase activator dichloroacetate could recover running distance, supporting their hypothesis that the suppression of pyruvate dehydrogenase activity by amino acid supplementation reduced muscle endurance. Although a highprotein diet is a well-known stimulus for increased skeletal muscle content in healthy subjects, it may deteriorate renal function in those with mild renal insufficiency.10 The creatinine clearance in young 5/6 nephrectomized mice fed a high-protein diet did not differ from that in mice fed on low protein in this study, but the creatinine clearance may not fully reflect the renal function in mice with different amounts of muscle volume. More precise measurement of glomerular filtration rate would help clarify the relationship between renal function and muscle endurance. To clarify the reason behind the altered mitochondria content in skeletal muscles in mice with chronic renal insufficiency, the authors demonstrated that serum tumor necrosis factor-a and 8-hydroxydeoxyguanosine levels were increased in 5/6 nephrectomized mice and that stimulation with tumor necrosis factor-a and interleukin-6 as well as acrolein and 4-hydroxynonenal, which are mediators of oxidative stress, reduced PGC-1a expression and increased B-cell lymphoma 2/adenovirus E1B 19 kDa protein-interacting protein 3-like (BNIP3L) expression in C2C12 myocytes, resulting in reduced mitochondria content. The successful demonstration of reduced mitochondria content in cultured myocytes exposed to inflammatory cytokines or oxidative stressors gives valuable insight into the in vivo mechanism linking chronic renal insufficiency and skeletal muscle impairment. Analyzing the effect of accumulated uremic toxins on muscle volume may also be beneficial. Previous reports analyzing the skeletal muscle mitochondria in CKD patients are conflicting. One report showed that skeletal muscle mitochondrial function was preserved in six 1259
commentary
patients on dialysis,11 whereas another report showed that patients with stage 3 or 4 CKD exhibited a reduction of mitochondria in skeletal muscle.12 The latter report also showed that exercise training increases muscle mitochondrial content in patients with CKD,12 which might account for the diversity of mitochondria content in patients with CKD. More detailed study of the mechanisms linking muscle volume and endurance reduction in CKD may benefit patients and provide a useful clinical strategy to maintain physical activity in CKD patients. DISCLOSURE
The authors declared no competing interests. REFERENCES 1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
1260
Fried LF, Lee JS, Shlipak M et al. Chronic kidney disease and functional limitation in older people: health, aging and body composition study. J Am Geriatr Soc 2006; 54: 750–756. Rajan VR, Mitch WE. Muscle wasting in chronic kidney disease: the role of the ubiquitin proteasome system and its clinical impact. Pediatr Nephrol 2008; 23: 527–535. Workeneh B, Bajaj M. The regulation of muscle protein turnover in diabetes. Int J Biochem Cell Biol 2013; 45: 2239–2244. Toledo FG, Goodpaster BH. The role of weight loss and exercise in correcting skeletal muscle mitochondrial abnormalities in obesity, diabetes and aging. Mol Cell Endocrinol 2013; 379: 30–34. Sugden MC, Holness MJ. Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDKs. Am J Physiol Endocrinol Metab 2003; 284: E855–E862. Thomson DM. Winder WW. AMP-activated protein kinase control of fat metabolism in skeletal muscle. Acta Physiol 2009; 196: 147–154. Tamaki M, Miyashita K, Wakino S et al. Chronic kidney disease reduces muscle mitochondria and exercise endurance and its exacerbation by dietary protein through inactivation of pyruvate dehydrogenase. Kidney Int 2014; 85: 1330–1339. Ma IJ, Fogo AB. Model of robust induction of glomerulosclerosis in mice: importance of genetic background. Kidney Int 2003; 64: 350–355. Meireles CL, Price SR, Pereira AM et al. Nutrition and chronic renal failure in rats: what is an optimal dietary protein? J Am Soc Nephrol 1999; 10: 2367–2373. Knight EL, Stampfer MJ, Hankinson SE et al. The impact of protein intake on renal function decline in women with normal renal function or mild renal insufficiency. Ann Intern Med 2003; 138: 460–467. Miro´ O, Marrades RM, Roca J et al. Skeletal muscle mitochondrial function is preserved in young patients with chronic renal failure. Am J Kidney Dis 2002; 39: 1025–1031. Balakrishnan VS, Rao M, Menon V et al. Resistance training increases muscle mitochondrial biogenesis in patients with chronic kidney disease. Clin J Am Soc Nephrol 2010; 5: 996–1002.
see basic research on page 1340
Enigmatic Cassandra: renal FGF23 formation in polycystic kidney disease Florian Lang1 and Michael Fo¨ller1 Fibroblast growth factor 23 (FGF23) counteracts phosphate excess and tissue calcification. Phosphate intake, Ca2 þ , parathyroid hormone, and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) stimulate FGF23 release from bone. FGF23 inhibits renal 1,25(OH)2D3 formation and phosphate reabsorption. Spichtig and colleagues demonstrate that FGF23 is generated in rodent polycystic kidneys, leading to an increase in plasma FGF23 concentration before reduction in kidney function. FGF23 fails to appreciably downregulate renal phosphate transporter and 1a-25OH-vitamin D hydroxylase activities. Unraveling underlying mechanisms may open diagnostic and therapeutic opportunities. Kidney International (2014) 85, 1260–1262. doi:10.1038/ki.2013.534
Fibroblast growth factor 23 (FGF23), a hormone produced mainly in bone and to a lesser extent in the spleen and brain, participates in the regulation of calcium and phosphate metabolism.1 FGF23 decreases the plasma concentration of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) by downregulating the 1,25(OH)2D3producing renal 1a-25OH-vitamin D hydroxylase (Cyp27b1) and by upregulating the catabolizing 1,25-hydroxyvitamin D3 24-hydroxylase (Cyp24a1).1 1,25(OH)2D3 increases plasma Ca2 þ and phosphate concentrations in part by stimulating intestinal absorption and renal reabsorption of calcium and phosphate. Furthermore, FGF23 is itself a powerful direct regulator of renal phosphate transport fostering renal phosphate elimination.1 Thus, FGF23 serves to prevent phosphate overload. For its effects on the kidney, FGF23 requires Klotho.1 Mice lacking functional FGF23 or Klotho suffer 1 Department of Physiology, University of Tu¨bingen, Tu¨bingen, Germany Correspondence: Florian Lang, Department of Physiology, University of Tu¨bingen, Gmelinstrasse 5, D-72076, Tu¨bingen, Germany. E-mail: [email protected]
from excessive increases in plasma phosphate, calcium, and 1,25(OH)2D3 levels, leading to decrease of bone density, growth retardation, severe vascular calcification, cardiac hypertrophy, osteopenia, emphysema, hypogonadism with infertility, hearing loss, and cognition impairment as well as thymus, fat, and skeletal muscle atrophy.1 The multiple severe disorders result in a dramatic decrease of lifespan.1 The tissue calcification in these mice is not simply the result of CaHPO4 supersaturation but is also driven by stimulation of osteogenic signaling.2 FGF23 release is markedly stimulated by 1,25(OH)2D3, and the excessive 1,25(OH)2D3 plasma concentrations in Klotho-deficient mice are followed by an increase in FGF23 plasma levels. Thus, FGF23 release is regulated by negative-feedback loops involving both phosphate and 1,25(OH)2D3 (Figure 1). FGF23 plasma concentrations are similarly elevated in patients suffering from chronic kidney disease (CKD).1 Notably, plasma FGF23 levels increase before plasma phosphate concentrations and before development of Kidney International (2014) 85
7.
8.
9.
associated chronic renal failure. Am J Physiol Renal Physiol 2009; 297: F410–F419. Yuan P, Xue H, Zhou L et al. Rescue of mesangial cells from high glucose-induced over-proliferation and extracellular matrix secretion by hydrogen sulfide. Nephrol Dial Transplant 2011; 26: 2119–2126. Lee HJ, Mariappan MM, Feliers D et al. Hydrogen sulfide inhibits high glucose-induced matrix protein synthesis by activating AMPactivated protein kinase in renal epithelial cells. J Biol Chem 2012; 287: 4451–4461. Triptara P, Patel NSA, Collino M et al. Generation of endogenous hydrogen sulfide by cystathionine gamma-lyase limits renal
10.
11.
12.
ischemia/reperfusion injury and dysfunction. Lab Invest 2008; 88: 1038–1048. Bos EM, Wang R, Snijder PM et al. Cystathionine gamma-lyase protects against renal ischemia/reperfusion by modulation oxidative stress. J Am Soc Nephrol 2013; 24: 759–770. Della Coletta Francescato H, Cunha FQ, Costa RS et al. Inhibition of hydrogen sulphide formation reduces cisplatin-induced renal damage. Nephrol Dial Transplant 2011; 26: 479–488. Song K, Wang F, Li Q et al. Hydrogen sulfide inhibits the renal fibrosis of obstructive nephropathy. Kidney Int 2014; 85: 1318–1329.
see basic research on page 1330
Decrease of muscle volume in chronic kidney disease: the role of mitochondria in skeletal muscle Hideki Yokoi1 and Motoko Yanagita1 Reduced muscle volume and impaired exercise endurance are welldocumented phenomena in chronic kidney disease, and the relevant molecular mechanisms have been gradually unveiled. Tamaki et al. demonstrate a reduction of mitochondria content in skeletal muscles as a novel mechanism of reduced exercise endurance in renal insufficiency. In addition, they show that a high-protein diet reduces exercise endurance through an inhibition of muscle pyruvate dehydrogenase. Kidney International (2014) 85, 1258–1260. doi:10.1038/ki.2013.539
Physical activity plays a major role in patient mortality and morbidity; however, exercise performance and endurance are known to decline in patients with chronic kidney disease (CKD).1 These individuals are at a higher risk for cardiovascular diseases because of this reduced exercise performance and endurance. Previous studies have shown that increased levels of inflammatory cytokines are associated with decreased mobility and subsequent development of disabilities due to a deterioration of muscle strength. To 1
Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan Correspondence: Motoko Yanagita, Department of Nephrology, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. E-mail: [email protected] 1258
date, efforts have been made to reveal the molecular mechanisms involved in the association between decreased muscle volume and CKD. Muscle mass reduction is considered to be due, at least in part, to an imbalance in protein synthesis and degradation via the ubiquitin–proteasome system,2 acid– base imbalance,3 insulin resistance,3 inflammation, and decreased exercise ability. The insulin-like growth factor I (IGF-I)/insulin receptor substrate 1 (IRS-1)/phosphatidylinositol 3-kinase (PI3K)/Akt pathway is considered a key pathway in protein degradation.2,3 Activation of the PI3K/Akt pathway supports multiple mechanisms for cellular proliferation, apoptosis inhibition, cellular migration, and cytoskeletal organization. The Akt protein family of serine/threonine kinases is
central to the regulation of and adaptation to many cellular stress-induced processes. Decreased Akt phosphorylation activates the ubiquitin pathway, which promotes muscle volume reduction through caspase-3 activation. In CKD, the E3 ubiquitin-conjugating enzyme is activated to promote protein degradation. Two ubiquitin ligases, atrogin-1/muscle atrophin F-box (MAFbx) and muscle ring finger 1 (MuRF1), are specifically expressed in muscle tissues and are known to correlate with muscle atrophy. Furthermore, caspase-3 activation gives rise to expression of a 14-kDa actin fragment, a potential marker of muscle mass reduction (Figure 1). Mitochondria are highly differentiated subcellular organelles that produce adenosine triphosphate (ATP) via oxidative phosphorylation.4 They are essential organelles that maintain the muscle mobility necessary for physical activity. Exercise endurance is closely associated with mitochondria concentrations in muscle tissues and electron transport complex activity. ATP is also produced by glycolysis and the tricarboxylic acid cycle. Pyruvate dehydrogenase regulates the entry of glycolytic products into the tricarboxylic acid cycle via oxidative decarboxylation of pyruvate to acetylcoenzyme A in the mitochondria of mammalian cells. Several studies have reported a decrease in pyruvate dehydrogenase activity in rat muscles in response to fasting and in diabetic models.5 In contrast, exercise- or contraction-induced increases in pyruvate dehydrogenase activity have been demonstrated in both human and rat models.5 Pyruvate dehydrogenase is considered to be a key enzyme responsible for switching from anaerobic to aerobic carbohydrate metabolism. AMP-activated protein kinase (AMPK) is a key regulator that inactivates acetyl-coenzyme A carboxylase, thereby promoting fatty acid oxidation and mitochondrial biogenesis.6 Administration of 5-aminoimidazole-4carboxamide ribonucleoside (AICAR), an AMPK activator, to rats results in increased skeletal muscle citrate synthase and cytochrome c activity, suggesting an increased amount of mitochondria. One Kidney International (2014) 85
commentary
Renal insufficiency Uremic toxin
Oxidative stress pAMPK
Renal insufficiency + high-protein diet
Inflammation
PGC-1α
PDH
? Mitochondrial amount Cleaved caspase-3 At early phase
Exercise endurance Cleaved caspase-3
At late phase
Muscle volume
Muscle power
Muscle atrophy
Figure 1 | Decrease of muscle volume in renal insufficiency. In subtotally nephrectomized mice, inflammatory cytokines and oxidative stress were elevated in the plasma, which reduced peroxisome proliferator-activated receptor-g coactivator-1a (PGC-1a) and phosphorylated AMP-activated protein kinase (AMPK). Young mice with renal insufficiency exhibited decreased mitochondrial content and reduced exercise endurance but maintained muscle volume and power. In contrast, aged mice with 5/6 nephrectomy showed reduced muscle volume and power as well as decreased mitochondrial amount and muscle endurance. Subtotally nephrectomized mice fed a high-protein diet exhibited a reduction of pyruvate dehydrogenase (PDH) activity in skeletal muscle, leading to a reduction in mitochondrial amount and exercise endurance.
of the mechanisms by which AMPK regulates the expression of mitochondrial enzymes involves regulating various transcription factors, including peroxisome proliferator-activated receptor-g coactivator-1a (PGC-1a), which is considered to be the vital regulator of mitochondrial content in mammalian tissues (Figure 1). PGC-1a was originally shown to induce mitochondrial biogenesis in cultured myocytes. Furthermore, PGC-1a overexpression in skeletal muscles increases type I fiber activity and subsequent resistance to muscle fatigue. In addition to the above-mentioned molecular mechanisms, Tamaki et al.7 (this issue) clarify a new mechanism in the reduction of exercise endurance and muscle volume in mice with renal insufficiency by focusing on the decrease of muscle mitochondria. Although the C57BL/6 strain is well known to be resistant against renal insufficiency after 5/6 nephrectomy,8 the authors successfully developed mice with renal insufficiency in this study. They investigated age differences in muscle volume and found that young mice with 5/6 nephrectomy showed a decrease in mitochondria content in type I (slow oxidative) and IIa (fast oxidative glycolytic) skeletal muscles and a decrease in running distance, despite the preservation of muscle volume and Kidney International (2014) 85
strength. Type I fibers are characterized by increased mitochondria content and oxidative state. Young mice also showed an increase in 14-kDa actin fragment content and caspase-3 expression, indicating increased protein degradation in skeletal muscle. Furthermore, a reduction of PGC-1a and phosphorylated AMPK was also found in these mice, indicating decreased mitochondria content. In contrast, aged mice lost muscle volume and power, in addition to the reduction in skeletal muscle mitochondria content. The underlying mechanism by which aged mice lost muscle volume might be dependent on prolonged activation of the proteasome pathway. The authors further demonstrated that a high-protein diet increased muscle mass and strength but reduced muscle endurance as characterized by reduced mitochondria content and AMPK activation. A high-protein diet elicits the accumulation of lactate and the reduction of pyruvate dehydrogenase, leading to physical performance impairment that is probably due to oxidative stress. An earlier report also showed the deteriorative effect on body physique of a high-protein diet in renal failure: rats with chronic renal failure fed a highprotein diet exhibited reduced body weight and length compared with those
fed a normal-protein diet, because of anorexia, uremia, and acidosis.9 Lastly, the authors successfully demonstrated that the pyruvate dehydrogenase activator dichloroacetate could recover running distance, supporting their hypothesis that the suppression of pyruvate dehydrogenase activity by amino acid supplementation reduced muscle endurance. Although a highprotein diet is a well-known stimulus for increased skeletal muscle content in healthy subjects, it may deteriorate renal function in those with mild renal insufficiency.10 The creatinine clearance in young 5/6 nephrectomized mice fed a high-protein diet did not differ from that in mice fed on low protein in this study, but the creatinine clearance may not fully reflect the renal function in mice with different amounts of muscle volume. More precise measurement of glomerular filtration rate would help clarify the relationship between renal function and muscle endurance. To clarify the reason behind the altered mitochondria content in skeletal muscles in mice with chronic renal insufficiency, the authors demonstrated that serum tumor necrosis factor-a and 8-hydroxydeoxyguanosine levels were increased in 5/6 nephrectomized mice and that stimulation with tumor necrosis factor-a and interleukin-6 as well as acrolein and 4-hydroxynonenal, which are mediators of oxidative stress, reduced PGC-1a expression and increased B-cell lymphoma 2/adenovirus E1B 19 kDa protein-interacting protein 3-like (BNIP3L) expression in C2C12 myocytes, resulting in reduced mitochondria content. The successful demonstration of reduced mitochondria content in cultured myocytes exposed to inflammatory cytokines or oxidative stressors gives valuable insight into the in vivo mechanism linking chronic renal insufficiency and skeletal muscle impairment. Analyzing the effect of accumulated uremic toxins on muscle volume may also be beneficial. Previous reports analyzing the skeletal muscle mitochondria in CKD patients are conflicting. One report showed that skeletal muscle mitochondrial function was preserved in six 1259
commentary
patients on dialysis,11 whereas another report showed that patients with stage 3 or 4 CKD exhibited a reduction of mitochondria in skeletal muscle.12 The latter report also showed that exercise training increases muscle mitochondrial content in patients with CKD,12 which might account for the diversity of mitochondria content in patients with CKD. More detailed study of the mechanisms linking muscle volume and endurance reduction in CKD may benefit patients and provide a useful clinical strategy to maintain physical activity in CKD patients. DISCLOSURE
The authors declared no competing interests. REFERENCES 1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
1260
Fried LF, Lee JS, Shlipak M et al. Chronic kidney disease and functional limitation in older people: health, aging and body composition study. J Am Geriatr Soc 2006; 54: 750–756. Rajan VR, Mitch WE. Muscle wasting in chronic kidney disease: the role of the ubiquitin proteasome system and its clinical impact. Pediatr Nephrol 2008; 23: 527–535. Workeneh B, Bajaj M. The regulation of muscle protein turnover in diabetes. Int J Biochem Cell Biol 2013; 45: 2239–2244. Toledo FG, Goodpaster BH. The role of weight loss and exercise in correcting skeletal muscle mitochondrial abnormalities in obesity, diabetes and aging. Mol Cell Endocrinol 2013; 379: 30–34. Sugden MC, Holness MJ. Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDKs. Am J Physiol Endocrinol Metab 2003; 284: E855–E862. Thomson DM. Winder WW. AMP-activated protein kinase control of fat metabolism in skeletal muscle. Acta Physiol 2009; 196: 147–154. Tamaki M, Miyashita K, Wakino S et al. Chronic kidney disease reduces muscle mitochondria and exercise endurance and its exacerbation by dietary protein through inactivation of pyruvate dehydrogenase. Kidney Int 2014; 85: 1330–1339. Ma IJ, Fogo AB. Model of robust induction of glomerulosclerosis in mice: importance of genetic background. Kidney Int 2003; 64: 350–355. Meireles CL, Price SR, Pereira AM et al. Nutrition and chronic renal failure in rats: what is an optimal dietary protein? J Am Soc Nephrol 1999; 10: 2367–2373. Knight EL, Stampfer MJ, Hankinson SE et al. The impact of protein intake on renal function decline in women with normal renal function or mild renal insufficiency. Ann Intern Med 2003; 138: 460–467. Miro´ O, Marrades RM, Roca J et al. Skeletal muscle mitochondrial function is preserved in young patients with chronic renal failure. Am J Kidney Dis 2002; 39: 1025–1031. Balakrishnan VS, Rao M, Menon V et al. Resistance training increases muscle mitochondrial biogenesis in patients with chronic kidney disease. Clin J Am Soc Nephrol 2010; 5: 996–1002.
see basic research on page 1340
Enigmatic Cassandra: renal FGF23 formation in polycystic kidney disease Florian Lang1 and Michael Fo¨ller1 Fibroblast growth factor 23 (FGF23) counteracts phosphate excess and tissue calcification. Phosphate intake, Ca2 þ , parathyroid hormone, and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) stimulate FGF23 release from bone. FGF23 inhibits renal 1,25(OH)2D3 formation and phosphate reabsorption. Spichtig and colleagues demonstrate that FGF23 is generated in rodent polycystic kidneys, leading to an increase in plasma FGF23 concentration before reduction in kidney function. FGF23 fails to appreciably downregulate renal phosphate transporter and 1a-25OH-vitamin D hydroxylase activities. Unraveling underlying mechanisms may open diagnostic and therapeutic opportunities. Kidney International (2014) 85, 1260–1262. doi:10.1038/ki.2013.534
Fibroblast growth factor 23 (FGF23), a hormone produced mainly in bone and to a lesser extent in the spleen and brain, participates in the regulation of calcium and phosphate metabolism.1 FGF23 decreases the plasma concentration of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) by downregulating the 1,25(OH)2D3producing renal 1a-25OH-vitamin D hydroxylase (Cyp27b1) and by upregulating the catabolizing 1,25-hydroxyvitamin D3 24-hydroxylase (Cyp24a1).1 1,25(OH)2D3 increases plasma Ca2 þ and phosphate concentrations in part by stimulating intestinal absorption and renal reabsorption of calcium and phosphate. Furthermore, FGF23 is itself a powerful direct regulator of renal phosphate transport fostering renal phosphate elimination.1 Thus, FGF23 serves to prevent phosphate overload. For its effects on the kidney, FGF23 requires Klotho.1 Mice lacking functional FGF23 or Klotho suffer 1 Department of Physiology, University of Tu¨bingen, Tu¨bingen, Germany Correspondence: Florian Lang, Department of Physiology, University of Tu¨bingen, Gmelinstrasse 5, D-72076, Tu¨bingen, Germany. E-mail: [email protected]
from excessive increases in plasma phosphate, calcium, and 1,25(OH)2D3 levels, leading to decrease of bone density, growth retardation, severe vascular calcification, cardiac hypertrophy, osteopenia, emphysema, hypogonadism with infertility, hearing loss, and cognition impairment as well as thymus, fat, and skeletal muscle atrophy.1 The multiple severe disorders result in a dramatic decrease of lifespan.1 The tissue calcification in these mice is not simply the result of CaHPO4 supersaturation but is also driven by stimulation of osteogenic signaling.2 FGF23 release is markedly stimulated by 1,25(OH)2D3, and the excessive 1,25(OH)2D3 plasma concentrations in Klotho-deficient mice are followed by an increase in FGF23 plasma levels. Thus, FGF23 release is regulated by negative-feedback loops involving both phosphate and 1,25(OH)2D3 (Figure 1). FGF23 plasma concentrations are similarly elevated in patients suffering from chronic kidney disease (CKD).1 Notably, plasma FGF23 levels increase before plasma phosphate concentrations and before development of Kidney International (2014) 85
