Sarcolipin Signaling Promotes Mitochondrial Biogenesis and Oxidative Metabolism in Skeletal Muscle

Maurya, Santosh K.; Herrera, Juan López de; Sahoo, Sanjaya Kumar; Reis, Felipe C.G.; Vega, Rick B.; Kelly, Daniel P.; Periasamy, Muthu

doi:10.1016/j.celrep.2018.08.036

Cited by 100 publications

(95 citation statements)

References 72 publications

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“…39 Genetic ablation of the Sln gene is associated with higher levels of glycolytic enzymes, including phosphofructokinase 1, hexokinase II, pyruvate kinase muscle, and pyruvate dehydrogenase. 40 It remains to be determined whether the reduction in SLN protein expression observed in the vastus lateralis may have facilitated the expression of glycolytic enzymes, as reported in previous research. 41,42…”

Section: Sarcolipin Protein Expression Is Not Altered By Short-termmentioning

confidence: 87%

Sarcolipin expression in human skeletal muscle: Influence of energy balance and exercise

Morales-Álamo

Martinez‐Canton²,

Gelabert‐Rebato

et al. 2019

Scandinavian Med Sci Sports

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Sarcolipin (SLN) is a SERCA uncoupling protein associated with exercise performance and lower adiposity in mice. To determine SLN protein expression in human skeletal muscle and its relationship with adiposity, resting energy expenditure (REE), and performance, SLN was assessed by Western blot in 199 biopsies from two previous studies. In one study, 15 overweight volunteers underwent a pretest followed by 4 days of caloric restriction and exercise (45‐minute one‐arm cranking + 8‐hour walking), and 3 days on a control diet. Muscle biopsies were obtained from the trained and non‐exercised deltoid, and vastus lateralis (VL). In another study, 16 men performed seven sessions of 4‐6 × 30‐sec all‐out sprints on the cycle ergometer with both limbs, and their VL and triceps brachii biopsied pre‐ and post‐training. SLN expression was twofold and 44% higher in the VL than in the deltoids and triceps brachii, respectively. SLN was associated with neither adiposity nor REE, and was not altered by a severe energy deficit (5500 kcal/day). SLN and cortisol changes after the energy deficit were correlated (r = .38, P = .039). SLN was not altered by low‐intensity exercise in the overweight subjects, whereas it was reduced after sprint training in the other group. The changes in SLN with sprint training were inversely associated with the changes in gross efficiency (r = −.59, P = .016). No association was observed between aerobic or anaerobic performance and SLN expression. In conclusion, sarcolipin appears to play no role in regulating the fat mass of men. Sprint training reduces sarcolipin expression, which may improve muscle efficiency.

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Section: Sarcolipin Protein Expression Is Not Altered By Short-termmentioning

confidence: 87%

Sarcolipin expression in human skeletal muscle: Influence of energy balance and exercise

Morales-Álamo

Martinez‐Canton²,

Gelabert‐Rebato

et al. 2019

Scandinavian Med Sci Sports

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“…[2][3][4][5][6][7][8] Activation of these transcriptional factors enhanced mitochondrial biogenesis leads to dramatically increased endurance, ameliorated insulin resistance in obesity, and type 2 diabetes. [9][10][11][12][13] It has been known that mitochondrial dysfunction and cellular oxidative stress induced by excess energy states and elevations in circulating free fatty acid (FFA) are associated with insulin resistance in skeletal muscle. [14][15][16][17][18][19][20] Therefore, in order to improve skeletal muscle insulin resistance and energy expenditure, it is important to stimulate mitochondrial biogenesis to preserve mitochondrial pool and to increase mitochondrial oxidative phosphorylation and FFA metabolism.…”

Section: Introductionmentioning

confidence: 99%

Astaxanthin stimulates mitochondrial biogenesis in insulin resistant muscle via activation of AMPK pathway

Nishida

Nawaz

Kado

et al. 2020

J cachexia sarcopenia muscle

110

125

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Background Skeletal muscle is mainly responsible for insulin‐stimulated glucose disposal. Dysfunction in skeletal muscle metabolism especially during obesity contributes to the insulin resistance. Astaxanthin (AX), a natural antioxidant, has been shown to ameliorate hepatic insulin resistance in obese mice. However, its effects in skeletal muscle are poorly understood. The current study aimed to investigate the molecular target of AX in ameliorating skeletal muscle insulin resistance. Methods We fed 6‐week‐old male C57BL/6J mice with normal chow (NC) or NC supplemented with AX (NC+AX) and high‐fat‐diet (HFD) or HFD supplemented with AX for 24 weeks. We determined the effect of AX on various parameters including insulin sensitivity, glucose uptake, inflammation, kinase signaling, gene expression, and mitochondrial function in muscle. We also determined energy metabolism in intact C2C12 cells treated with AX using the Seahorse XFe96 Extracellular Flux Analyzer and assessed the effect of AX on mitochondrial oxidative phosphorylation and mitochondrial biogenesis. Results AX‐treated HFD mice showed improved metabolic status with significant reduction in blood glucose, serum total triglycerides, and cholesterol (p< 0.05). AX‐treated HFD mice also showed improved glucose metabolism by enhancing glucose incorporation into peripheral target tissues, such as the skeletal muscle, rather than by suppressing gluconeogenesis in the liver as shown by hyperinsulinemic–euglycemic clamp study. AX activated AMPK in the skeletal muscle of the HFD mice and upregulated the expressions of transcriptional factors and coactivator, thereby inducing mitochondrial remodeling, including increased mitochondrial oxidative phosphorylation component and free fatty acid metabolism. We also assessed the effects of AX on mitochondrial biogenesis in the siRNA‐mediated AMPK‐depleted C2C12 cells and showed that the effect of AX was lost in the genetically AMPK‐depleted C2C12 cells. Collectively, AX treatment (i) significantly ameliorated insulin resistance and glucose intolerance through regulation of AMPK activation in the muscle, (ii) stimulated mitochondrial biogenesis in the muscle, (iii) enhanced exercise tolerance and exercise‐induced fatty acid metabolism, and (iv) exerted antiinflammatory effects via its antioxidant activity in adipose tissue. Conclusions We concluded that AX treatment stimulated mitochondrial biogenesis and significantly ameliorated insulin resistance through activation of AMPK pathway in the skeletal muscle.

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“…RNA‐Seq analysis revealed a number of genes that were highly up‐regulated in MKO EDL muscle, including Sln , Ankrd1 , and Pak1 . SLN regulates SERCA activity and promotes mitochondrial biogenesis and oxidative metabolism in response to increased energy demand, improving endurance and muscle performance . SLN has been reported to be up‐regulated in mouse models of Duchenne muscular dystrophy and various myopathies, suggesting that SLN up‐regulation may be a general response to increased metabolic demand under conditions of compromised muscle function to improve oxidative metabolism.…”

Section: Discussionmentioning

confidence: 99%

Myopalladin promotes muscle growth through modulation of the serum response factor pathway

Filomena

Yamamoto

Caremani

et al. 2019

J cachexia sarcopenia muscle

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Background Myopalladin (MYPN) is a striated muscle‐specific, immunoglobulin‐containing protein located in the Z‐line and I‐band of the sarcomere as well as the nucleus. Heterozygous MYPN gene mutations are associated with hypertrophic, dilated, and restrictive cardiomyopathy, and homozygous loss‐of‐function truncating mutations have recently been identified in patients with cap myopathy, nemaline myopathy, and congenital myopathy with hanging big toe. Methods Constitutive MYPN knockout (MKO) mice were generated, and the role of MYPN in skeletal muscle was studied through molecular, cellular, biochemical, structural, biomechanical, and physiological studies in vivo and in vitro. Results MKO mice were 13% smaller compared with wild‐type controls and exhibited a 48% reduction in myofibre cross‐sectional area (CSA) and significantly increased fibre number. Similarly, reduced myotube width was observed in MKO primary myoblast cultures. Biomechanical studies showed reduced isometric force and power output in MKO mice as a result of the reduced CSA, whereas the force developed by each myosin molecular motor was unaffected. While the performance by treadmill running was similar in MKO and wild‐type mice, MKO mice showed progressively decreased exercise capability, Z‐line damage, and signs of muscle regeneration following consecutive days of downhill running. Additionally, MKO muscle exhibited progressive Z‐line widening starting from 8 months of age. RNA‐sequencing analysis revealed down‐regulation of serum response factor (SRF)‐target genes in muscles from postnatal MKO mice, important for muscle growth and differentiation. The SRF pathway is regulated by actin dynamics as binding of globular actin to the SRF‐cofactor myocardin‐related transcription factor A (MRTF‐A) prevents its translocation to the nucleus where it binds and activates SRF. MYPN was found to bind and bundle filamentous actin as well as interact with MRTF‐A. In particular, while MYPN reduced actin polymerization, it strongly inhibited actin depolymerization and consequently increased MRTF‐A‐mediated activation of SRF signalling in myogenic cells. Reduced myotube width in MKO primary myoblast cultures was rescued by transduction with constitutive active SRF, demonstrating that MYPN promotes skeletal muscle growth through activation of the SRF pathway. Conclusions Myopalladin plays a critical role in the control of skeletal muscle growth through its effect on actin dynamics and consequently the SRF pathway. In addition, MYPN is important for the maintenance of Z‐line integrity during exercise and aging. These results suggest that muscle weakness in patients with biallelic MYPN mutations may be associated with reduced myofibre CSA and SRF signalling and that the disease phenotype may be aggravated by exercise.

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Sarcolipin Signaling Promotes Mitochondrial Biogenesis and Oxidative Metabolism in Skeletal Muscle

Cited by 100 publications

References 72 publications

Sarcolipin expression in human skeletal muscle: Influence of energy balance and exercise

Sarcolipin expression in human skeletal muscle: Influence of energy balance and exercise

Astaxanthin stimulates mitochondrial biogenesis in insulin resistant muscle via activation of AMPK pathway

Myopalladin promotes muscle growth through modulation of the serum response factor pathway

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