scholarly journals Deficits in the Skeletal Muscle Transcriptome and Mitochondrial Coupling in Progressive Diabetes-Induced CKD Relate to Functional Decline

2021 ◽  
Author(s):  
Daniel C. Bittel ◽  
Adam J. Bittel ◽  
Arun S. Varadhachary ◽  
Terri Pietka ◽  
David R. Sinacore
Keyword(s):  
Skeletal Muscle ◽  
Electron Transport ◽  
Physical Function ◽  
Functional Decline ◽  
Treatment Strategies ◽  
Muscle Performance ◽  
Transcriptional Networks ◽  
Ckd Progression ◽  
Muscle Energetics ◽  
Transport Chain

Two-thirds of those with type-2 diabetes (T2DM) have or will develop chronic kidney disease (CKD), characterized by rapid renal decline that, together with superimposed T2DM-related metabolic sequelae, synergistically promote early frailty and mobility-deficits that increases risk of mortality. Distinguishing the mechanisms linking renal decline to mobility deficits in CKD progression and/or increasing severity in T2DM is instrumental in both identifying those at high-risk for functional decline, and in formulating effective treatment strategies to prevent renal failure. While evidence suggests that skeletal muscle energetics may relate to the development of these comorbidities in advanced-CKD, this has never been assessed across the spectrum of CKD progression, especially in T2DM-induced CKD. Here, using next-gen sequencing, we first report significant downregulation in transcriptional networks governing oxidative phosphorylation, coupled electron-transport, electron-transport-chain(ETC)-complex assembly, and mitochondrial organization in both middle- and late-stage CKD in T2DM. Furthermore, muscle mitochondrial coupling is impaired as early as stage 3-CKD, with additional deficits in ETC-respiration, enzymatic activity, and increased redox-leak. Moreover, mitochondrial ETC function and coupling strongly related to muscle performance, and physical function. Our results indicate that T2DM-induced CKD progression impairs physical function, with implications for altered metabolic transcriptional networks and mitochondrial functional deficits, as primary mechanistic factors early in CKD-progression in T2DM.

scholarly journals Deficits in the Skeletal Muscle Transcriptome and Mitochondrial Coupling in Progressive Diabetes-Induced CKD Relate to Functional Decline

2021 ◽  
Author(s):  
Daniel C. Bittel ◽  
Adam J. Bittel ◽  
Arun S. Varadhachary ◽  
Terri Pietka ◽  
David R. Sinacore
Keyword(s):  
Skeletal Muscle ◽  
Electron Transport ◽  
Physical Function ◽  
Functional Decline ◽  
Treatment Strategies ◽  
Muscle Performance ◽  
Transcriptional Networks ◽  
Ckd Progression ◽  
Muscle Energetics ◽  
Transport Chain

Two-thirds of those with type-2 diabetes (T2DM) have or will develop chronic kidney disease (CKD), characterized by rapid renal decline that, together with superimposed T2DM-related metabolic sequelae, synergistically promote early frailty and mobility-deficits that increases risk of mortality. Distinguishing the mechanisms linking renal decline to mobility deficits in CKD progression and/or increasing severity in T2DM is instrumental in both identifying those at high-risk for functional decline, and in formulating effective treatment strategies to prevent renal failure. While evidence suggests that skeletal muscle energetics may relate to the development of these comorbidities in advanced-CKD, this has never been assessed across the spectrum of CKD progression, especially in T2DM-induced CKD. Here, using next-gen sequencing, we first report significant downregulation in transcriptional networks governing oxidative phosphorylation, coupled electron-transport, electron-transport-chain(ETC)-complex assembly, and mitochondrial organization in both middle- and late-stage CKD in T2DM. Furthermore, muscle mitochondrial coupling is impaired as early as stage 3-CKD, with additional deficits in ETC-respiration, enzymatic activity, and increased redox-leak. Moreover, mitochondrial ETC function and coupling strongly related to muscle performance, and physical function. Our results indicate that T2DM-induced CKD progression impairs physical function, with implications for altered metabolic transcriptional networks and mitochondrial functional deficits, as primary mechanistic factors early in CKD-progression in T2DM.

Palmitate increases superoxide production through mitochondrial electron transport chain and NADPH oxidase activity in skeletal muscle cells

2008 ◽  
Vol 216 (3) ◽  
pp. 796-804 ◽  
Author(s):  
Rafael Herling Lambertucci ◽  
Sandro Massao Hirabara ◽  
Leonardo dos Reis Silveira ◽  
Adriana Cristina Levada‐Pires ◽  
Rui Curi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Electron Transport ◽  
Nadph Oxidase ◽  
Oxidase Activity ◽  
Electron Transport Chain ◽  
Muscle Cells ◽  
Superoxide Production ◽  
Mitochondrial Electron Transport Chain ◽  
Nadph Oxidase Activity ◽  
Transport Chain

scholarly journals Sarcolipin overexpression improves muscle energetics and reduces fatigue

2015 ◽  
Vol 118 (8) ◽  
pp. 1050-1058 ◽  
Author(s):  
Danesh H. Sopariwala ◽  
Meghna Pant ◽  
Sana A. Shaikh ◽  
Sanjeewa A. Goonasekera ◽  
Jeffery D. Molkentin ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Performance ◽  
Force Frequency ◽  
Frequency Curve ◽  
Muscle Energetics ◽  
Store Operated Calcium Entry ◽  
Flexor Digitorum Brevis ◽  
Flexor Digitorum ◽  
Muscle Contractile ◽  
Frequency Curves

Sarcolipin (SLN) is a regulator of sarcoendoplasmic reticulum calcium ATPase in skeletal muscle. Recent studies using SLN-null mice have identified SLN as a key player in muscle thermogenesis and metabolism. In this study, we exploited a SLN overexpression ( Sln OE) mouse model to determine whether increased SLN level affected muscle contractile properties, exercise capacity/fatigue, and metabolic rate in whole animals and isolated muscle. We found that Sln OE mice are more resistant to fatigue and can run significantly longer distances than wild-type (WT). Studies with isolated extensor digitorum longus (EDL) muscles showed that Sln OE EDL produced higher twitch force than WT. The force-frequency curves were not different between WT and Sln OE EDLs, but at lower frequencies the pyruvate-induced potentiation of force was significantly higher in Sln OE EDL. SLN overexpression did not alter the twitch and force-frequency curve in isolated soleus muscle. However, during a 10-min fatigue protocol, both EDL and soleus from Sln OE mice fatigued significantly less than WT muscles. Interestingly, Sln OE muscles showed higher carnitine palmitoyl transferase-1 protein expression, which could enhance fatty acid metabolism. In addition, lactate dehydrogenase expression was higher in Sln OE EDL, suggesting increased glycolytic capacity. We also found an increase in store-operated calcium entry (SOCE) in isolated flexor digitorum brevis fibers of Sln OE compared with WT mice. These data allow us to conclude that increased SLN expression improves skeletal muscle performance during prolonged muscle activity by increasing SOCE and muscle energetics.

scholarly journals Avian and Mammalian Skeletal Muscle Mitochondrial Enzyme and Electron Transport Chain Activities

2012 ◽  
Vol 26 (S1) ◽  
Author(s):  
Sarah Kuzmiak ◽  
Doree Gardner ◽  
Patrick Pangle ◽  
Haley McInnis ◽  
Wayne T. Willis
Keyword(s):  
Skeletal Muscle ◽  
Electron Transport ◽  
Electron Transport Chain ◽  
Mammalian Skeletal Muscle ◽  
Mitochondrial Enzyme ◽  
Transport Chain

scholarly journals Klotho: An Emerging Factor With Ergogenic Potential

2022 ◽  
Vol 2 ◽  
Author(s):  
Eliott Arroyo ◽  
Ashley D. Troutman ◽  
Ranjani N. Moorthi ◽  
Keith G. Avin ◽  
Andrew R. Coggan ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Physical Function ◽  
Muscle Function ◽  
Treatment Strategies ◽  
Functional Independence ◽  
Therapeutic Interventions ◽  
Older Individuals ◽  
Dietary Interventions ◽  
Lifestyle Modifications ◽  
Skeletal Muscle Function

Sarcopenia and impaired cardiorespiratory fitness are commonly observed in older individuals and patients with chronic kidney disease (CKD). Declines in skeletal muscle function and aerobic capacity can progress into impaired physical function and inability to perform activities of daily living. Physical function is highly associated with important clinical outcomes such as hospitalization, functional independence, quality of life, and mortality. While lifestyle modifications such as exercise and dietary interventions have been shown to prevent and reverse declines in physical function, the utility of these treatment strategies is limited by poor widespread adoption and adherence due to a wide variety of both perceived and actual barriers to exercise. Therefore, identifying novel treatment targets to manage physical function decline is critically important. Klotho, a remarkable protein with powerful anti-aging properties has recently been investigated for its role in musculoskeletal health and physical function. Klotho is involved in several key processes that regulate skeletal muscle function, such as muscle regeneration, mitochondrial biogenesis, endothelial function, oxidative stress, and inflammation. This is particularly important for older adults and patients with CKD, which are known states of Klotho deficiency. Emerging data support the existence of Klotho-related benefits to exercise and for potential Klotho-based therapeutic interventions for the treatment of sarcopenia and its progression to physical disability. However, significant gaps in our understanding of Klotho must first be overcome before we can consider its potential ergogenic benefits. These advances will be critical to establish the optimal approach to future Klotho-based interventional trials and to determine if Klotho can regulate physical dysfunction.

scholarly journals Alterations of skeletal muscle bioenergetics in a mouse with F508del mutation leading to a cystic fibrosis-like condition

2019 ◽  
Vol 317 (2) ◽  
pp. E327-E336
Author(s):  
Nicola Lai ◽  
Chinna Kummitha ◽  
Mitchell Drumm ◽  
Charles Hoppel
Keyword(s):  
Skeletal Muscle ◽  
Cystic Fibrosis ◽  
Creatine Kinase ◽  
Electron Transport ◽  
Oxidative Phosphorylation ◽  
Aerobic Capacity ◽  
Electron Transport Chain ◽  
Kinase Activity ◽  
Creatine Kinase Activity ◽  
Transport Chain

High energy expenditure is reported in cystic fibrosis (CF) animal models and patients. Alterations in skeletal muscle oxidative capacity, fuel utilization, and the creatine kinase-phosphocreatine system suggest mitochondrial dysfunction. Studies were performed on congenic C57BL/6J and F508del ( Cftrtm1kth) mice. Indirect calorimetry was used to measure gas exchange to evaluate aerobic capacity during treadmill exercise. The bioenergetic function of skeletal muscle subsarcolemmal (SSM) and interfibrillar mitochondria (IFM) was evaluated using an integrated approach combining measurement of the rate of oxidative phosphorylation by polarography and of electron transport chain activities by spectrophotometry. CF mice have reduced maximal aerobic capacity. In SSM of these mice, oxidative phosphorylation was impaired in the presence of complex I, II, III, and IV substrates except when glutamate was used as substrate. This impairment appeared to be caused by a defect in complex V activity, whereas the oxidative system of the electron transport chain was unchanged. In IFM, oxidative phosphorylation and electron transport chain activities were preserved, whereas complex V activity was reduced, in CF. Furthermore, creatine kinase activity was reduced in both SSM and IFM of CF skeletal muscle. The decreased complex V activity in SSM resulted in reduced oxidative phosphorylation, which could explain the reduced skeletal muscle response to exercise in CF mice. The decrease in mitochondrial creatine kinase activity also contributed to this poor exercise response.

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