Metabolic Basis and Pathogenesis of Skeletal Muscle Dysfunction as Cause of Frailty in Chronic Kidney Disease

Chronic disease is the major cause of excess mortality [1], disability adjusted life years lost [2], and health care costs [3, 4], and frailty contributes to each of these adverse outcomes [5‒7]. Six in ten US adults have at least one chronic disease, as do more than 75% of US workers [4, 8]. Fifteen percent of noninstitutionalized persons aged 65 and older fit frailty criteria [9] and longer lives lived by persons with chronic disease are often less healthy because of age-related frailty [10].

Physical or phenotypic frailty is one of two conceptual frameworks for frailty (the other is deficit accumulation frailty) across chronic diseases [11], of which skeletal muscle dysfunction is a key component (Fig. 1) [12]. Skeletal muscle dysfunction in frailty might be mediated by decreased muscle mass [12] and/or decreased performance of surviving muscle [13]. This review details current knowledge of the metabolic basis for the skeletal muscle contribution to phenotypic frailty that to date has been largely defined by observation [14]. Although frailty accompanies many chronic conditions [9], commonly aging [15], we will use chronic kidney disease (CKD) to explore mechanisms for its associated skeletal muscle dysfunction that are common to, and possibly distinct from, aging.

Phenotypic frailty in adults includes self-reported fatigue, weakness, slowness of movement including slow gait speed, low overall activity, and occasionally unintentional weight loss (Fig. 1) [16]. It is a multidimensional phenomenon that reflects declining physical function and vulnerability to stress such as illness or hospitalization [16]. Patients with non-dialysis-dependent CKD can have gait abnormalities [17] and a higher risk of frailty or diminished physical function [18]. Those who are dialysis-dependent have decreased exercise capacity and decreased muscle strength [19]. Additionally, physical activity and gait speed declined over time in patients who were dialysis-dependent [20] and those with lower estimated glomerular filtration rate (eGFR) had slower gait speed, lower gait scores, and those with lower gait scores had greater fall risk [21]. Notably, among the components of frailty [16], gait speed most strongly predicted mortality in patients with CKD on hemodialysis [20]. Although some studies showed that baseline 25-hydroxy vitamin D, NT-pro-BNP, creatinine, or cystatin C did not consistently correlate with baseline physical performance or its rate of change in patients with CKD followed for 24 months [22], others showed that frailty was associated with cystatin C-based eGFR, it worsened as CKD progressed [23] and was more pronounced in patients with end-stage kidney disease than those who were not non-dialysis-dependent [24]. These latter data suggest that several commonly measured biomarkers in patients with CKD might be associated but insufficient to predict physical function decline.

Sarcopenia describes degenerative loss of skeletal muscle mass, quality, and strength [25, 26]. It can be part of the frailty phenotype [25] and comprises age-related decline in skeletal muscle mass [27‒29]. Cumulative effects of sarcopenia range from decreased physical activity to include decreased mobility, disability, falls, repeated hospitalizations [30], and increased mortality [29]. Frailty and sarcopenia are distinct conditions [31]. Supporting this distinction, only about 2/3 of frail individuals have skeletal muscle dysfunction, suggesting that frailty phenotype is much broader and represents clinical manifestation of multiple organ system functional impairment (Fig. 2) [32], the latter being characteristic of CKD [18]. Sarcopenia is often accompanied by intramuscular adipose tissue accumulation that is associated with low muscle quality and reduced physical performance and frailty in older adults [33]. The presence and degree of sarcopenia can be determined structurally by assessing muscle mass or functionally by assessing physical performance as with repeated chair stand time or quantifying gait speed [34]. Most clinically actionable information, like changes in skeletal muscle mass and overall metabolic state, can be gleaned with noninvasive methods such that there is currently little enthusiasm for routine skeletal muscle biopsy in patients with frailty including sarcopenia [35].

Sarcopenia severity can be assessed in outpatients by muscle quantity (e.g., mid-arm or mid-calf circumference), by muscle strength (e.g., handgrip), and by physical performance of muscle (e.g., sit-to-stand chair test and/or by gait speed) [36]. Contributors to reduced muscle mass mediated by increased muscle protein catabolism in animals include the insulin/insulin growth factor 1 (IGF-1)-Akt-mTOR and the ubiquitin-proteosome system [UPS] [37], upregulation of reactive oxygen species (ROS) [38, 39] and cytokines that induce myostatin production (causes muscle atrophy) [40], enhanced myostatin-induced expression of Foxo-dependent atrogenes (control muscle atrophy) [41], and metabolic acidosis (Table 1) [42, 43]. Contributors to reduced muscle mass mediated by decreased muscle protein synthesis in animals include upregulation of nucleolar protein 66 [44]. Reduced function of remaining muscle mass in patients can be mediated by impaired skeletal muscle mitochondrial function and metabolism and by CKD-related metabolic acidosis [45] and in animals by increased levels of glucocorticoids [46], angiotensin II [47], parathyroid hormone [48], and protein-bound uremic toxins (Table 1) [49].

Sarcopenia is common in patients with CKD [50‒55] and can be a component of its decreased physical function [52]. Although sarcopenia prevalence increases with aging [56], it is more prevalent in patients with CKD compared to similarly aged patients without CKD [57], CKD accelerates its symptoms [58], and its degree is associated with increased mortality in CKD [57]. Furthermore, the degree of sarcopenia is inversely associated with eGFR [59], and sarcopenia worsens as CKD progresses [60, 61]. In addition, sarcopenia was most pronounced in pre-dialysis patients with CKD than in those who had begun dialysis, suggesting that dialysis was associated with improvement [62]. Sarcopenia was present in 34.5% of patients with CKD 2 and 3a but in 65.5% with CKD 3b to 5 [54]. The degree of sarcopenia in patients with CKD receiving hemodialysis associated directly with reduced ability to perform basic and instrumental activities of daily living [63].

Some mediators of sarcopenia in patients with CKD including uremic toxins [64] and ubiquitination related to metabolic acidosis [65] might be distinct from those causing frailty in aging. Other mediators, on the other hand, appear to be common to patients with declining kidney function and aging-related frailty. These include inflammation [54], oxidative stress [66], insulin resistance [67], and physical inactivity [68].

Approaching frailty through a CKD lens is supported by the recognition that patients with CKD have a comparably high prevalence of frailty relative to patients with other chronic diseases [69]. When assessed with the Short Physical Performance Battery (SPPB) instrument, 55% of patients with CKD stage 4–5 were frail [70], compared with 52.6% of patients who were preoperative for coronary artery disease-related or cardiac heart valve-related surgery [71], 38% with cirrhosis [72], and 30.8% with chronic obstructive pulmonary disease (COPD) [73]. The CKD cause, e.g., diabetes, might add to the risk for, or to the degree of, frailty in individuals with CKD [74]. Although frailty incidence increases with aging [15], accompanying CKD further increases frailty incidence so that those with CKD have a greater frailty incidence than comparably aged individuals without CKD [18, 75]. Indeed, individuals with the comparatively preserved eGFR of CKD stages 2 and 3 had higher frailty symptom burden including loss of muscle strength, tiredness, bone/joint pain, and reduced quality of life measured with the health-related quality of life (HRQoL) instrument than age-matched controls without CKD [76].

Phenotypic frailty encompasses the full CKD spectrum, including patients with non-dialysis-dependent CKD [77], those on hemodialysis [78] or peritoneal dialysis [79], and those with a kidney transplant [80]. Increased albuminuria itself defines CKD [81] and higher levels in individuals with metabolic syndrome are associated with increased frailty risk [82]. Furthermore, higher albuminuria levels within the range of “normal” are associated with increased risk of frailty in community-dwelling middle-aged and older individuals [83]. Patients with CKD have abnormal skeletal muscle structure including myofibrillar degeneration [84] and decreased skeletal muscle performance including decreased muscle strength, which likely contributed to their functional limitations [85]. In addition to reducing well-being, phenotypic frailty in CKD [30] contributes to increased mortality [18, 86], low employment prevalence [87, 88], and adversely affects timing of the initiation of kidney replacement therapy [89].

Aging includes gradual deterioration of repair processes [90] and patients with CKD likewise have compromised repair processes, including reduced mitochondrial autophagy [91‒93]. As such, CKD has been described as a model of premature aging in animals and patients and includes low-grade inflammation, accumulation of uremic toxins including metabolic acids, increased cellular senescence, and impaired mitochondrial biogenesis [94].

Physical activity is reduced in individuals with CKD when compared to those without CKD [95‒101], it decreases further in those with non-dialysis-dependent CKD as CKD progresses to more advanced stages [99] and their level of physical activity is inversely associated with their level of frailty [102]. Sedentary behavior generally appears to be a contributing factor to phenotypic frailty in patients not known to have CKD [103]. Like in aging patients without CKD, low physical activity in patients with CKD might lead to metabolic changes that cause phenotypic frailty, including increased oxidative stress in neutrophils [104], increased insulin resistance [105], increased skeletal muscle inflammation [106], and decreased skeletal muscle mitochondrial capacity [106, 107], volume and strength [108], and regenerative capacity [109, 110]. On the other hand, regular exercise improved physical fitness and walking capacity for patients with non-dialysis-dependent CKD [111].

Malnutrition increased the risk for frailty in aged individuals not known to have CKD [112] such that 2 of 3 malnourished older adults were frail, but less than 10% who were frail were malnourished [113]. Likewise, malnourished compared to non-malnourished patients with CKD were more likely to be frail [114]. Nutrient intake that is inadequate for nutritional needs constitutes malnutrition; however, additional CKD-associated factors, like metabolic acidosis, impaired insulin/insulin-like growth factor-1 signaling pathways, uremic toxins, and systemic inflammation can increase protein catabolism, causing the inflammatory state of protein-energy wasting (PEW), reflecting loss of somatic and circulating body protein and energy reserves [115]. PEW can be associated with sarcopenia [36], and cachexia is its most severe stage [116]. Less than 2% of patients with CKD 1–2 have PEW, 11–54% with stages 3–5 do [116], and 30–70% of patients on hemodialysis have PEW with reduced muscle mass [117, 118] associated with decreased muscle strength [119], poor physical functioning [120], fatigue [121], and increased mortality [122, 123]. These data show that compromised nutrition is common in phenotypic frailty of both aging and CKD but is more prevalent in CKD.

Sarcopenic and frail patients not known to have CKD commonly have low levels of IGF-1 [124] and those with CKD commonly have resistance to IGF-1 effect, due in part to accumulation of insulin growth factor-binding proteins that are normally cleared by the kidney [125]. Insulin resistance in aging patients is associated with frailty [126‒128] and is linked to sarcopenia [126]. Likewise, insulin resistance is common in patients with CKD [129‒131] and skeletal muscle insulin resistance in patients with CKD leads to decreased skeletal muscle mitochondrial energy production with increased production of ROS [132]. These data show that insulin resistance commonly accompanies phenotypic frailty of aging and CKD.

In aging individuals without CKD, low vitamin D levels are associated with loss of muscle mass [133] and strength [134]. Likewise, patients with CKD commonly have low vitamin D levels [135], and its low levels were associated with frailty in patients with dialysis-dependent CKD [136]. In addition, vitamin D deficiency can upregulate the UPS pathway leading to protein degradation with skeletal muscle atrophy in rats [137], potentially contributing to phenotypic frailty.

Serum testosterone levels decrease with age [138] and in CKD [139]. Testosterone effects to increase muscle protein synthesis are modulated by several factors including genetic background, nutrition, and exercise [140]. Testosterone supplementation attenuated some sarcopenic characteristics such as decrease in grip strength [141] and muscle mass [142]. Supraphysiological treatment for 6 months with testosterone in a placebo-controlled study increased leg lean body mass and leg and arm strength [143]. Although high testosterone doses significantly increased strength in elderly males [143], risks including thrombosis, sleep apnea, and increased prostate cancer risk appear to outweigh the benefits.

Mitochondrial dysfunction appears to be a determinant for frailty associated with aging-related diseases [144]. Aged individuals with frailty have reduced skeletal muscle mitochondrial density [145], commonly have impaired mitochondrial function and impaired biogenesis that mediate sarcopenia [145] and have poor physical performance with chronic fatigue [144]. Among aged individuals, lower mitochondrial capacity and efficiency were both associated with slower walking speed [146]. Suggesting it as a frailty cause, skeletal muscle mitochondrial function was impaired in pre-frail individuals [147], and frail compared to non-frail individuals had faster exercise-induced decline of high-energy phosphate that correlated with exercise intolerance [13].

Patients with dialysis-dependent [148] and non-dialysis-dependent CKD [149] have fewer skeletal muscle mitochondria, possibly mediated by disordered mitochondrial biosynthesis [150, 151], leading to a net mitochondrial decrease and likely decreased overall oxygen utilization. In addition, mitochondrial dysfunction appears to be a determinant for frailty associated with CKD [148], as described for other aging-related diseases [144]. Furthermore, patients with CKD have skeletal muscle abnormalities in specific enzymes and metabolic pathways related to mitochondrial energy generation [152, 153].

Mitochondrial dysfunction in skeletal muscle of patients with CKD was associated with poor physical performance, greater intramuscular adipose tissue, and increased markers of inflammation and oxidative stress [154]. Also, patients with CKD had less lower leg muscle oxidative capacity that was directly associated with eGFR and with lower physical performance assessed by the 6-min walk test [45]. The degree of CKD-associated inflammation, oxidative stress, and low physical performance directly associated with skeletal muscle mitochondrial dysfunction in patients with non-dialysis-dependent CKD [154]. Furthermore, low serum bicarbonate concentration, a surrogate for metabolic acidosis, associated with skeletal muscle dysfunction in patients with non-dialysis-dependent CKD [45]. These data support that skeletal muscle mitochondrial dysfunction is a common feature of frailty in aging and CKD.

Aged individuals eating acid-producing, Western-type diets can have low-grade metabolic acidosis [155]. With their age-associated lower eGFRs [155], the incidence and severity of metabolic acidosis increases as CKD progresses [156]. Metabolic acidosis is associated with low-grade inflammation [157] and in patients with CKD, it contributes to reduced muscle mass [42, 43] and reduced muscle function [45] of advanced CKD stages. Decreased muscle mass in patients with CKD is due in part to increased muscle protein catabolism induced by metabolic acidosis [158] through upregulation of the UPS [65]. Indeed, low serum bicarbonate concentration ([HCO₃⁻]) in patients is associated with functional limitation [159] including slower gait speed [160].

Factors associated with metabolic acidosis in patients with CKD that contribute to phenotypic frailty include impaired skeletal muscle mitochondrial function and metabolism [45]. Impaired mitochondrial autophagy suggests a mechanism by which metabolic acidosis in CKD exacerbates mitochondrial dysfunction, disrupts energy production, and decreases muscle function in animals and patients [91, 93, 94]. Animals with metabolic acidosis had reduced kidney mitochondrial oxidative phosphorylation efficiency with mild respiratory uncoupling in kidney, but not liver, mitochondria [161], suggesting disproportionate sensitivity to metabolic acidosis in kidney mitochondria (Fig. 3). Chronic metabolic acidosis was associated with more rapid development of exertional muscle fatigue in patients with CKD [162] and leg muscle oxidative capacity in patients with CKD was directly associated with serum [HCO₃⁻] [45].

Body acid challenges less severe on the continuum of acid stress [163] than metabolic acidosis might also lead to skeletal muscle dysfunction. Increased dietary acid can cause phenomena associated with skeletal muscle dysfunction including oxidative stress [164], insulin resistance [165, 166], and increased level of inflammatory cytokines [164] (see below).

Aging persons with frailty [167] and nonaged persons with CKD [148] had increased oxidative stress and mitochondrial dysfunction, and increased serum markers of oxidative stress associated directly with frailty [168, 169] and slower gait speed [170]. Kidneys are organs with high metabolic demands and so are highly dependent upon mitochondrial energy production, making them susceptible to producing ROS [171]. Indeed, patients with reduced eGFR have oxidative stress [172] which can injure mitochondria that require ongoing repair. As indicated, this repair process can be compromised in patients with CKD [91, 93, 94]. In addition, oxidative stress in an animal CKD model limited the repair component of the ongoing process of skeletal muscle breakdown and repair, leading to a net decrease in muscle mass [172]. Oxidative stress is another common feature of the frailty of aging and CKD.

Insulin resistance is associated with increased frailty risk in aging individuals [128], is considered a precursor of frailty in individuals not known to have CKD [173], and as indicated, is common in patients with CKD [129‒131]. Insulin suppresses degradation of cellular proteins through the IRS-1/phosphatidylinositol 3-kinase (PI3K)/protein kinase B pathway [174] and resistance to its action leads to protein breakdown in patients, decreasing skeletal muscle mass [175]. Insulin resistance in patients is associated with decreased microvascular vasodilatory response [176], possibly limiting the necessary enhanced blood flow to muscles in response to increased physical activity. Metabolic acidosis in CKD inhibits insulin signaling [177] and augments insulin resistance in CKD [178]. The degree of metabolic acidosis in patients with non-dialysis-dependent CKD predicted the presence of insulin resistance and low serum [HCO₃⁻] was an independent variable for insulin-mediated glucose disposal rate in patients with CKD [179], supporting that metabolic acidosis contributes to insulin resistance in CKD (Fig. 3).

Cytokines intrinsic to skeletal muscle cells (myokines) regulate muscle mass and function and can be influenced by aging and stress [180]. The inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) were elevated in frail aged adults and predicted their mortality [181]. Serum levels of these two inflammatory cytokines were elevated in patients with CKD and higher still in those with more advanced CKD [182]. Furthermore, each of these cytokines caused skeletal muscle breakdown and were increased in skeletal muscle of mouse models of CKD [183], but myostatin inhibition reduced their blood levels [184]. In addition, TNF-α and IL-6 infusion caused muscle atrophy in mice that attenuated when these cytokines were neutralized [184]. Furthermore, TNF-α activated myostatin in mice, leading to upregulation of UPS-mediated catabolism [184]. Upregulation of these two inflammatory cytokines characterizes frailty associated with both aging and CKD. Overall, patients with CKD have increased systemic [185] and skeletal muscle [85] inflammation and pro-inflammatory cytokines have been implicated in the muscle wasting process of CKD [186, 187].

The putative uremic toxins indoxyl sulfate (IS) and p-cresyl sulfate accumulate in skeletal muscle of mice 6–10-fold compared to other tissues, and their skeletal muscle levels correlate linearly with severity of muscle atrophy in these animals [188]. Even low levels of IS and p-cresyl sulfate reduce myogenic differentiation by inhibiting myogenin expression and promoting fibro-adipogenic differentiation in cultured mouse myocytes [189], suggesting that sarcopenia can progress at even early CKD stages. Mouse myoblasts treated with IS exhibit mitochondrial dysfunction with membrane potential decrease, leading to autophagy and muscle loss, reducing skeletal muscle functional capacity [190]. Suggesting that these in vitro findings have clinical correlates, patients with dialysis-dependent CKD, serum levels of IS inversely associated with muscle mass and strength [191].

Current understanding of the shared metabolic features that mediate skeletal muscle dysfunction across common conditions like aging and CKD highlight avenues for further research to identify interventions that reduce frailty, thereby adding to interventions like exercise and dialysis that already do so. Metabolic disturbances common to aging and CKD whose correction might reduce frailty include those related to decreased physical activity, mitochondrial dysfunction, acid stress, oxidative stress, insulin resistance, and inflammation. Identification of disturbances improved by dialysis that reduce frailty might lead to development of conservative CKD management interventions other than dialysis that correct these factors. Such conservative management strategies might become routine components of care for non-dialysis-dependent patients with CKD, leading to prevention of frailty.

Phenotypic frailty is common in patients with CKD and is associated with multiple adverse consequences including increased mortality and decreased quality of life. Recognition of its metabolic basis can identify research targets to help develop additional treatment/prevention strategies, particularly non-dialysis, conservative management strategies. Further testing will determine if these interventions successfully treat and/or prevent frailty in CKD. If so, clinicians are likely to more routinely test for frailty in patients with CKD, particularly in those with early stages, followed by institution of management strategies to improve it when detected or prevent it in those who are currently frailty free.

The authors acknowledge the contributions of discussions with Drs. Matthew Abramowitz and Cynthia Delgado to the development of this manuscript. The authors would like to thank Dr. Jun Shao for the design of figures and the table.

Dr. D.E. Wesson, Dr. V. Mathur, and Dr. N. Tangri were paid consultants to Tricida, Inc. in connection with the development of this manuscript. Dr. D.E. Wesson and Dr. N. Tangri report consultancy and personal fees from Tricida, Inc. Dr. V. Mathur is a member of advisory boards at Tricida and listed on patents related to work for Tricida, and reports stock or stock options in Tricida. Dr. V. Mathur reports additional consulting fees from Tricida, Equillium, Myovant, Rigel, Corvidia, Acuta, Frazier, Intarcia, PTC Bio, and Sanifit outside the submitted work.

There was no funding provided in the development of this manuscript.

Donald E. Wesson conceived the idea for the manuscript, gathered and reviewed most of the included background publications with their interpretation, conducted the discussions with Drs. Abramowitz and Delgado, wrote the initial draft, and reviewed and edited all revisions for important intellectual content, and submitted the manuscript after review and approval by Vandana Mathur and Navdeep Tangri.

Vandana Mathur gathered and reviewed additional background publications and their interpretation, reviewed and edited the initial draft and all subsequent revisions for important intellectual content, and submitted drafts of the table and figures.

Navdeep Tangri gathered and reviewed additional background publications with their interpretations, reviewed and edited the initial draft and all subsequent revisions for important intellectual content, and submitted drafts of the figures.