Molecular changes in skeletal muscle in chronic kidney disease: A systematic review

Muscle weakness and atrophy are important manifestations of multiple sclerosis (MS). To investigate the pathophysiological mechanisms of skeletal muscle change in MS, we induced experimental autoimmune encephalomyelitis (EAE) in Lewis male rats and examined morphological and molecular changes in skeletal muscle. We also treated EAE rats with calpepetin, a calpain inhibitor, to examine its beneficial effects on skeletal muscle damage. Morphological changes in muscle tissue of EAE rats included smaller and irregularly shaped muscle fibers and fibrosis. Western blot analysis demonstrated increased calpain:calpastatin ratio, inflammation-related transcription factors (nuclear factor-κB:inhibitor of κB α ratio), and proinflammatory enzymes (cyclooxygenase-2). TUNEL-positive myonuclei in skeletal muscle cells of EAE rats indicated cell death. In addition, markers of apoptotic cell death (Bax:Bcl-2 ratio and caspase-12 protein levels) were elevated. Expression of muscle-specific ubiquitin ligases (muscle atrophy F-box and muscle ring finger protein 1), was upregulated in muscle tissue of EAE-vehicle animals. Both prophylactic and therapeutic treatment with calpeptin partially attenuated muscle changes noted in EAE animals. These results indicate that morphological and molecular changes including apoptotic cell death and protein breakdown develop in skeletal muscle of EAE animals and that these changes can be reversed by calpain inhibition.

Oxidative Phenotype Protects Myofibers from Pathological Insults Induced by Chronic Heart Failure in Mice

Perceived knowledge among patients cared for by nephrologists about chronic kidney disease and end-stage renal disease therapies

Exercise intolerance is a cardinal feature of heart failure with preserved ejection fraction and so far exercise training (ET) is the most effective treatment. Since the improvement in exercise capacity is only weakly associated with changes in diastolic function other mechanisms, like changes in the skeletal muscle, contribute to improvement in peak oxygen consumption. The aim of the present study was to analyze molecular changes in skeletal muscle of patients with heart failure with preserved ejection fraction performing different ET modalities. Skeletal muscle biopsies were taken at study begin and after 3 and 12 months from patients with heart failure with preserved ejection fraction randomized either into a control group (guideline based advice for ET), a high-intensity interval training group (HIIT) or a moderate continuous training group. The first 3 months of ET were supervised in-hospital followed by 9 months home-based ET. Protein and mRNA expression of atrophy-related proteins, enzyme activities of enzymes linked to energy metabolism and satellite cells (SCs) were quantified. Exercise capacity improved 3 months after moderate continuous exercise training and HIIT. This beneficial effect was lost after 12 months. HIIT mainly improved markers of energy metabolism and the amount and function of SC, with minor changes in markers for muscle atrophy. Only slight changes were observed after moderate continuous exercise training. The molecular changes were no longer detectable after 12 months. Despite similar improvements in exercise capacity by HIIT and moderate continuous exercise training after 3 months, only HIIT altered proteins related to energy metabolism and amount/function of SC. These effects were lost after switching from in-hospital to at-home-based ET. URL: https://www. gov; Unique identifier: NCT02078947.

Prolonged unloading of skeletal muscle, a common outcome of events such as spaceflight, bed rest and hindlimb unloading, can result in extensive metabolic, structural and functional changes in muscle fibres. With advancement in investigations of cellular and molecular mechanisms, understanding of disuse muscle atrophy has significantly increased. However, substantial gaps exist in our understanding of the processes dictating muscle plasticity during unloading, which prevent us from developing effective interventions to combat muscle loss. This review aims to update the status of knowledge and underlying mechanisms leading to cellular and molecular changes in skeletal muscle during unloading. We have also discussed advances in the understanding of contractile dysfunction during spaceflights and in ground-based models of muscle unloading. Additionally, we have elaborated on potential therapeutic interventions that show promising results in boosting muscle mass and strength during mechanical unloading. Finally, we have identified key gaps in our knowledge as well as possible research direction for the future.

Paraneoplastic conditions such as cancer cachexia are often exacerbated by chemotherapy, which affects the patient’s quality of life as well as the response to therapy. The aim of this narrative review was to overview the body-composition-related changes and molecular effects of different chemotherapy agents used in cancer treatment on skeletal-muscle remodeling. A literature search was performed using the Web of Science, Scopus, and Science Direct databases and a total of 77 papers was retrieved. In general, the literature survey showed that the molecular changes induced by chemotherapy in skeletal muscle have been studied mainly in animal models and mostly in non-tumor-bearing rodents, whereas clinical studies have essentially assessed changes in body composition by computerized tomography. Data from preclinical studies showed that chemotherapy modulates several molecular pathways in skeletal muscle, including the ubiquitin–proteasome pathway, autophagy, IGF-1/PI3K/Akt/mTOR, IL-6/JAK/STAT, and NF-κB pathway; however, the newest chemotherapy agents are underexplored. In conclusion, chemotherapy exacerbates skeletal-muscle wasting in cancer patients; however, the incomplete characterization of the chemotherapy-related molecular effects on skeletal muscle makes the development of new preventive anti-wasting strategies difficult. Therefore, further investigation on molecular mechanisms and clinical studies are necessary.

Although disorders of mineral metabolism and skeletal muscle are common in chronic kidney disease (CKD), their potential relationship remains unexplored. Elevations in plasma phosphate, parathyroid hormone, and fibroblastic growth factor 23 together with decreased calcitriol levels are common features of CKD. High-phosphate intake is a major contributor to progression of CKD. This study was primarily aimed to determine the influence of high-phosphate intake on muscle and to investigate whether calcitriol supplementation counteracts negative skeletal muscle changes associated with long-term uremia. Proportions and metabolic and morphological features of myosin-based muscle fiber types were assessed in the slow-twitch soleus and the fast-twitch tibialis cranialis muscles of uremic rats (5/6 nephrectomy, Nx) and compared with sham-operated (So) controls. Three groups of Nx rats received either a standard diet (0.6% phosphorus, Nx-Sd), or a high-phosphorus diet (0.9% phosphorus, Nx-Pho), or a high-phosphorus diet plus calcitriol (10 ng/kg 3 day/wk ip, Nx-Pho + Cal) for 12 wk. Two groups of So rats received either a standard diet or a high-phosphorus diet (So-Pho) over the same period. A multivariate analysis encompassing all fiber-type characteristics indicated that Nx-Pho + Cal rats displayed skeletal muscle phenotypes intermediate between Nx-Pho and So-Pho rats and that uremia-induced skeletal muscle changes were of greater magnitude in Nx-Pho than in Nx-Sd rats. In uremic rats, treatment with calcitriol preserved fiber-type composition, cross-sectional size, myonuclear domain size, oxidative capacity, and capillarity of muscle fibers. These data demonstrate that a high-phosphorus diet potentiates and low-dose calcitriol attenuates adverse skeletal muscle changes in long-term uremic rats.

ContextPrimary hyperparathyroidism leads to hypercalcemia and muscle dysfunction. Muscle weakness is associated with increased morbidity and mortality but is overlooked in surgical treatment guidelines. While parathyroidectomy is the only curative treatment, its effects on skeletal muscle strength and molecular remodeling remain underexplored.ObjectiveDetermining functional and molecular changes in skeletal muscle before and after parathyroidectomy.MethodsA prospective observational study was conducted in the spring and fall of 2023. Patients underwent surgery at the Endocrine and Sarcoma unit at the Karolinska University Hospital in Stockholm, Sweden. A total of 21 postmenopausal women with primary hyperparathyroidism planned for surgery were included, whereof 15 completed the study protocol. Participants had no disabling comorbidities. Muscle function tests, muscle biopsies, MRI, and biochemical panels were analyzed before and after parathyroidectomy. Muscle composition of m. vastus lateralis was tested with MRI and transcriptomic analysis of muscle biopsies. Leg strength was evaluated with timed stands test and peak torque tests. Activity level was estimated from questionnaires.ResultsParathyroidectomy normalized calcium levels (P < .001) and improved muscle strength (P < .005). Muscle volume increased (P = .023) and fat fraction was reduced (P = .013), without changes in physical activity levels. Transcriptomic analysis identified 981 differentially expressed genes postsurgery, enriched in pathways mirroring exercise-induced adaptations.ConclusionThese findings highlight the impact of parathyroidectomy on skeletal muscle function and suggest that muscle assessments should be included in surgical referral criteria to address age-related muscle decline and improve long-term outcomes.

Cytopathology of the motor neuron

Chronic kidney disease (CKD) is a progressive damage of kidneys that can no longer serve the blood-filtering function, and is a life-threatening condition. Skeletal muscle wasting is a common complication of CKD. Yet the relationship between kidney and skeletal muscle in CKD remains unclear. Exosomes, a type of small membrane-bound vesicles released from cells to the extracellular environment, have increasingly received attention due to their potential as mediators of crosstalk between kidneys and different organs, including skeletal muscle. This mini-review summarizes the recent findings that point to the role of exosomes in the cross-talk between kidney and skeletal muscle in CKD. Understanding of the contents and the mechanism of exosome release may prone exosomes be the potential therapeutic targets for CKD.

A Decade After the KDOQI CKD Guidelines: Impact on the United States and Global Public Policy

Advanced chronic kidney disease (CKD) is characterized by a premature aging phenotype of multifactorial origin. Mitochondrial dysfunction is prevalent in CKD and has been proposed as a major contributor to poor muscle function. Although the mitochondria-derived peptides (MDPs) humanin and mitochondrial open reading frame of 12S rRNA-c (MOTS-c) are involved in cell survival, suppression of apoptosis, and glucose control, the implications of MDP in CKD are unknown. We investigated humanin and MOTS-c protein expression in skeletal muscle and serum levels in CKD at stage 5 (glomerular filtration rate: <15 ml/min) patients and age-matched controls with normal renal function. Whereas circulating levels of humanin were increased in CKD, local muscle expression was reduced. In contrast, MOTS-c levels were reduced in both skeletal muscle and serum in CKD. Humanin in serum correlated positively to circulating TNF levels. Reduced MDP levels in skeletal muscle were associated with lower mitochondrial density and evidence of oxidative stress. These results indicate a differential regulation of MDPs in CKD and suggest an alternative site for humanin production than skeletal muscle in the uremic milieu. MDP levels were linked to systemic inflammation and evidence of oxidative stress in the muscle, two hallmark features of premature aging and uremia.

We aimed to examine cellular and molecular changes in skeletal muscle of recreationally active older women in response to 24 weeks of combined resistance training and N-3 PUFA-rich healthy diet. Sixty-three women (65-70 years) were randomized into resistance training and healthy diet rich in N-3PUFAs (RT-HD), resistance training only (RT) and controls (CON). Fiber type-specific morphological characteristics and gene expression of inflammatory biomarkers and regulators of muscle mass were analyzed in m. vastus lateralis biopsies obtained before the intervention and 4 days after the last training session. Gene expression of the proinflammatory cytokine IL-1β was downregulated (p < .05) and that of the regulator of cellular growth mTOR (p < 0.05) was upregulated in skeletal muscle of RT-HD only. There was also a significant hypertrophy of fast type IIA muscle fibers in RT-HD only (+23%, p < .05). In conclusion, resistance training combined to an N-3 PUFA-rich healthy diet but not alone triggers local anti-inflammatory and growth responses, favoring skeletal muscle hypertrophy in already recreationally active older women.

Spaceflight and bed rest (BR) lead to muscle atrophy. This study assessed the effect of essential amino acid (EAA) supplementation and resistance training with decreased energy intake on molecular changes in skeletal muscle after 28-day BR and 14-day recovery. Thirty-one men (31-55 years) subjected to an 8 ± 6% energy deficit were randomized to receive EAA without resistance training (AA, n = 7), or EAA 3 h after (RT, n = 12) or 5 min before (AART, n = 12) resistance training. During BR, myostatin transcript levels increased twofold in the AA group. During recovery, insulin-like growth factor-1 (IGF-1) mRNA increased in all groups, whereas Pax7, MyoD, myogenin, and MRF4 transcripts increased in AA only (all P < 0.05). MAFbx transcripts decreased twofold with AA and RT. Satellite cells did not change during BR or recovery. This suggests that EAA alone is the least protective countermeasure to muscle loss, and several molecular mechanisms are proposed by which exercise attenuates muscle atrophy during BR with energy deficit.

Muscle contractile and metabolic dysfunction is a common feature of sarcopenia of aging and chronic diseases: From sarcopenic obesity to cachexia