Muscle Abnormalities with Kidney Failure

CKD is accompanied by loss of muscle mass, and most patients have reduced muscle strength and endurance capacity affecting activities of daily life (1). The myopathy progresses with advanced kidney failure and during maintenance dialysis treatment. The pathophysiology is multifaceted; comorbidities, such as diabetes mellitus and cardiovascular disease, as well as the common catabolic factors inflammation and acidosis contribute to muscle wasting. In addition, evidence from animal studies implies that uremic toxicity attenuates muscle protein synthesis (2). Upregulation of the growth differentiation factor myostatin has been suggested as a pathogenetic factor leading to muscle atrophy (3). Factors related to a sedentary life and ageing, which occur prematurely in CKD, add to loss of function, reduced muscle mass, and frailty. Aerobic exercise capacity is impaired due to inadequate energy supply, and clinical and experimental studies of energy metabolism suggest a reduced mitochondrial oxidative capacity in muscle limiting endurance exercise (3). Direct measurement of mitochondrial function in patients is complicated; most methods used in clinical studies involve analysis of proxy markers.

The study by Souweine et al. (4), in this issue of CJASN, aims to elucidate some effects of uremic toxicity per se on muscle morphology and function. By selecting a group of patients on long-term hemodialysis without other factors affecting muscle function, such as comorbidities and wasting, specific uremia-related effects on muscle function and morphology were evaluated. These patients, apparently without sarcopenia, had significantly lower endurance capacity than matched controls, whereas muscle strength was similar in both groups. Muscle catabolism was not activated, as evaluated by western blotting analysis of the ubiquitin-proteasome pathway and activity of calpain and myostatin. Muscle composition was altered with a dominance of glycolytic type 2 fibers, a finding in contrast with the changes toward an increase of the oxidative type 1 fibers described in ageing and wasting as well as after a period of endurance training in healthy subjects (5).

Confirming earlier findings in patients on dialysis (1), lower mitochondrial density indicating reduced numbers was found. However, the amount of mitochondrial DNA and expression of mitochondrial transcription factors were similar in patients and controls. In patients with CKD with low muscle mass, conflicting evidence with low mitochondrial DNA has been reported. The authors describe structural abnormalities with enlarged swollen mitochondria and active autophagic and mitophagic processes as evaluated by electron microscopy and gene expression methods. The structural abnormalities translate into mitochondrial dysfunction as previously indicated by several animal studies and ³¹P magnetic resonance studies of muscle phosphocreatine recovery in patients with CKD (3).

Although some pathogenetic factors mentioned above are common to other chronic diseases, there are also obviously specific mechanisms in CKD causing muscular dysfunction (1). Controversial evidence exists regarding effects of microvascular abnormalities on skeletal muscle, and capillary density is reported to be normal or low. The role of endothelial (dys-)regulation of microcirculation in skeletal muscle remains to be elucidated. Glucose uptake and glycogen stores in muscle are low due to peripheral insulin resistance (6). Changes in intracellular signaling attenuate the effect of insulin on cellular bioenergetics and mitochondrial function. Alterations in lipid metabolism with increased levels of free fatty acids associate with lipotoxic effects and lipid accumulation in muscle (6).

The mitochondrial pyruvate dehydrogenase complex converts pyruvate to acetyl-CoA, which is entering the tricarboxylic acid cycle. Patients with CKD have low activity of pyruvate dehydrogenase complex, preventing the tricarboxylic acid cycle and thereby reducing ATP production in mitochondria. Decreased activity of mitochondrial oxidative enzymes has been demonstrated in muscle biopsies from patients with CKD (3). Accumulation of uremic toxins in muscle disrupts mitochondrial metabolism, resulting in uncoupling of oxidative phosphorylation. The reduced energy production is accompanied by increased formation of reactive oxygen species, which has detrimental effects in muscle, leading to a vicious circle inhibiting bioenergetic processes and enhancing apoptotic processes. In line with the findings of Souweine et al. (4), autophagy and mitophagy appear to be important features of uremic myopathy. Upregulation of proteins associated with autophagy has been found in animal experiments.

Mitochondria-derived peptides (MDPs), such as humanin and mitochondrial open reading frame of the 12S rRNA-c, are involved in cellular processes and intracellular signaling suppressing apoptosis. Circulating levels of MDPs are altered in CKD, and skeletal muscle expression of both these MDPs is reduced, suggesting a role in the apoptotic processes (7). Humanin also has effects on glucose uptake by enhancing insulin action.

Interventional studies investigating outcomes on muscle function and metabolism are scarce in CKD. Exercise training in patients with CKD improves physical function and exercise capacity (1). However, maximal oxygen uptake does not increase as expected due to peripheral factors in the large muscle groups. Conflicting evidence exists regarding the effects of physical training on mitochondrial mass and function. Balakrishnan et al. (8) found a significant increase in mitochondrial DNA, which was accompanied by increased area of type 1 and 2 muscle fibers after 12 weeks of resistance training in patients with moderate to severe CKD. Recently, Watson et al. (9) failed to show effects of endurance and resistance training on mitochondrial mass and mitochondrial biogenesis in patients with CKD. Gene expression studies in the same cohort showed minor effects on transcription factors involved in mitochondrial biogenesis. Resistance training in CKD also associates with improved glucose tolerance and less production of reactive oxygen species. Data on long-term exercise programs in patients with CKD and possible effects on muscle function and energy metabolism are lacking.

Although wasting and sarcopenia associate with undernutrition and dietary interventions are recommended in patients with CKD, the effect on muscle mass is limited (10). Nutritional support may prevent muscle loss, but if nutrition can restore sarcopenic muscles in patients with CKD is less clear. Specific effects of dietary interventions with so-called functional foods on energy metabolism have not been evaluated.

Pharmaceutical interventions may have a future role in protection of mitochondrial function. Carnitine deficiency is prevalent in CKD, and early studies have suggested that supplementation is beneficial in patients on dialysis. However, carnitine supplementation has no proven effect on muscle metabolism and function. Animal experiments suggest that compounds, such as antioxidants, microRNA modulators, ghrelin, and ursolic acid, and plant extracts, such as resveratrol, might have positive effects on muscle bioenergetics (3,10). There are no clinical data yet to support any of these interventions.

In summary, the study by Souweine et al. (4) reveals some specific features of muscle abnormalities in selected patients on long-term hemodialysis without apparent comorbid factors affecting muscle composition. In spite of maintained muscle mass and strength, the described phenotype with a relative reduction of oxidative type 1 fibers and loss of mitochondria explain at least in part the low endurance capacity encountered in this group. Still, our understanding of the fundamental pathophysiology underlying muscle dysfunction in CKD is incomplete, and so far, we have no clear first-line intervention to suggest for a major trial. Long-term exercise programs, including both resistance and endurance training, need to be evaluated. The findings in this study have potential implications for future trials because some interventions aiming at restoring muscle function may have positive effects in specific subgroups only. The learning is that detailed information regarding patient characteristics is crucial for understanding and interpretation of this complicated multifaceted clinical research area. Thus, muscle dysfunction in CKD is another future area where personalized precision medicine will be important for the well-being of our patients.

Disclosures

P. Bárány reports clinical trials with Alnylam, GSK, and Omeros.

Funding

None.