scholarly journals Mitochondrial dysfunction and consequences in calpain-3-deficient muscle

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Vanessa E. Jahnke ◽  
Jennifer M. Peterson ◽  
Jack H. Van Der Meulen ◽  
Jessica Boehler ◽  
Kitipong Uaesoontrachoon ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Function ◽  
Mitochondrial Activity ◽  
Calpain 3 ◽  
And Function ◽  
Deficient Mice

Abstract Background Nonsense or loss-of-function mutations in the non-lysosomal cysteine protease calpain-3 result in limb-girdle muscular dystrophy type 2A (LGMD2A). While calpain-3 is implicated in muscle cell differentiation, sarcomere formation, and muscle cytoskeletal remodeling, the physiological basis for LGMD2A has remained elusive. Methods Cell growth, gene expression profiling, and mitochondrial content and function were analyzed using muscle and muscle cell cultures established from healthy and calpain-3-deficient mice. Calpain-3-deficient mice were also treated with PPAR-delta agonist (GW501516) to assess mitochondrial function and membrane repair. The unpaired t test was used to assess the significance of the differences observed between the two groups or treatments. ANOVAs were used to assess significance over time. Results We find that calpain-3 deficiency causes mitochondrial dysfunction in the muscles and myoblasts. Calpain-3-deficient myoblasts showed increased proliferation, and their gene expression profile showed aberrant mitochondrial biogenesis. Myotube gene expression analysis further revealed altered lipid metabolism in calpain-3-deficient muscle. Mitochondrial defects were validated in vitro and in vivo. We used GW501516 to improve mitochondrial biogenesis in vivo in 7-month-old calpain-3-deficient mice. This treatment improved satellite cell activity as indicated by increased MyoD and Pax7 mRNA expression. It also decreased muscle fatigability and reduced serum creatine kinase levels. The decreased mitochondrial function also impaired sarcolemmal repair in the calpain-3-deficient skeletal muscle. Improving mitochondrial activity by acute pyruvate treatment improved sarcolemmal repair. Conclusion Our results provide evidence that calpain-3 deficiency in the skeletal muscle is associated with poor mitochondrial biogenesis and function resulting in poor sarcolemmal repair. Addressing this deficit by drugs that improve mitochondrial activity offers new therapeutic avenues for LGMD2A.

scholarly journals The Polyphenol Pterostilbene Ameliorates the Myopathic Phenotype of Collagen VI Deficient Mice via Autophagy Induction

2020 ◽  
Vol 8 ◽  
Author(s):  
Samuele Metti ◽  
Lisa Gambarotto ◽  
Martina Chrisam ◽  
Martina La Spina ◽  
Martina Baraldo ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Autophagic Flux ◽  
Collagen Vi ◽  
Beneficial Effects ◽  
Autophagy Induction ◽  
And Function ◽  
Cellular Components ◽  
Deficient Mice ◽  
Muscle Remodeling

The induction of autophagy, the catabolic pathway by which damaged or unnecessary cellular components are subjected to lysosome-mediated degradation and recycling, is impaired in Collagen VI (COL6) null mice and COL6-related myopathies. This autophagic impairment causes an accumulation of dysfunctional mitochondria, which in turn leads to myofiber degeneration. Our previous work showed that reactivation of autophagy in COL6-related myopathies is beneficial for muscle structure and function both in the animal model and in patients. Here we show that pterostilbene (Pt)—a non-toxic polyphenol, chemically similar to resveratrol but with a higher bioavailability and metabolic stability—strongly promotes in vivo autophagic flux in the skeletal muscle of both wild-type and COL6 null mice. Reactivation of autophagy in COL6-deficient muscles was also paralleled by several beneficial effects, including significantly decreased incidence of spontaneous apoptosis, recovery of ultrastructural defects and muscle remodeling. These findings point at Pt as an effective autophagy-inducing nutraceutical for skeletal muscle with great potential in counteracting the major pathogenic hallmarks of COL6-related myopathies, a valuable feature that may be also beneficial in other muscle pathologies characterized by defective regulation of the autophagic machinery.

scholarly journals PGC-1β prevents statin-associated myotoxicity in oxidative skeletal muscle

2017 ◽  
Author(s):  
François Singh ◽  
Joffrey Zoll ◽  
Urs Duthaler ◽  
Anne-Laure Charles ◽  
Gilles Laverny ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Rat Skeletal Muscle ◽  
Oxidative Defense ◽  
Muscle Types ◽  
And Function

AbstractStatins are generally well-tolerated, but can induce myopathy. Statins are associated with impaired expression of PGC-1β in human and rat skeletal muscle. The current study was performed to investigate the relation between PGC-1β expression and function and statin-associated myopathy. In WT mice, atorvastatin impaired mitochondrial function in glycolytic, but not in oxidative muscle. In PGC-1β KO mice, atorvastatin induced a shift from oxidative type IIA to glycolytic type IIB myofibers mainly in oxidative muscle and mitochondrial dysfunction was observed in both muscle types. In glycolytic muscle of WT and KO mice and in oxidative muscle of KO mice, atorvastatin suppressed mitochondrial proliferation and oxidative defense, leading to apoptosis. In contrast, mitochondrial function was maintained or improved and apoptosis decreased by atorvastatin in oxidative muscle of WT mice. In conclusion, PGC-1β has an important role in preventing damage to oxidative muscle in the presence of a mitochondrial toxicant such as atorvastatin.

scholarly journals Estradiol stimulates mitochondrial biogenesis and adiponectin expression in skeletal muscle

2014 ◽  
Vol 221 (3) ◽  
pp. 391-403 ◽  
Author(s):  
Gabriela Capllonch-Amer ◽  
Miquel Sbert-Roig ◽  
Bel M Galmés-Pascual ◽  
Ana M Proenza ◽  
Isabel Lladó ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Sexual Dimorphism ◽  
Sex Hormones ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Function ◽  
Female Rats ◽  
Metabolic Effects ◽  
Cultured Myotubes

Sexual dimorphism has been found in mitochondrial features of skeletal muscle, with female rats showing greater mitochondrial mass and function compared with males. Adiponectin is an insulin-sensitizing adipokine whose expression has been related to mitochondrial function and that is also expressed in skeletal muscle, where it exerts local metabolic effects. The aim of this research was to elucidate the role of sex hormones in modulation of mitochondrial function, as well as its relationship with adiponectin production in rat skeletal muscle. Anin vivostudy with ovariectomized Wistar rats receiving or not receiving 17β-estradiol (E2) (10 μg/kg per 48 h for 4 weeks) was carried out, in parallel with an assay of cultured myotubes (L6E9) treated with E2(10 nM), progesterone (Pg; 1 μM), or testosterone (1 μM). E2upregulated the markers of mitochondrial biogenesis and dynamics, and also of mitochondrial function in skeletal muscle and L6E9. Althoughin vivoE2supplementation only partially restored the decreased adiponectin expression levels induced by ovariectomy, these were enhanced by E2and Pg treatment in cultured myotubes, whereas testosterone showed no effects. Adiponectin receptor 1 expression was increased by E2treatment, bothin vivoandin vitro, but testosterone decreased it. In conclusion, our results are in agreement with the sexual dimorphism previously reported in skeletal muscle mitochondrial function and indicate E2to be its main effector, as it enhances mitochondrial function and diminishes oxidative stress. Moreover, our data support the idea of the existence of a link between mitochondrial function and adiponectin expression in skeletal muscle, which could be modulated by sex hormones.

scholarly journals Subpopulation-specific differences in skeletal muscle mitochondria in humans with obesity: insights from studies employing acute nutritional and exercise stimuli

2020 ◽  
Vol 318 (4) ◽  
pp. E538-E553
Author(s):  
Nisreen Wahwah ◽  
Katon A. Kras ◽  
Lori R. Roust ◽  
Christos S. Katsanos
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Function ◽  
Subcellular Location ◽  
Metabolic Dysfunction ◽  
Muscle Mitochondria ◽  
Skeletal Muscle Mitochondria ◽  
Experimental Approaches ◽  
And Function

Mitochondria from skeletal muscle of humans with obesity often display alterations with respect to their morphology, proteome, biogenesis, and function. These changes in muscle mitochondria are considered to contribute to metabolic abnormalities observed in humans with obesity. Most of the evidence describing alterations in muscle mitochondria in humans with obesity, however, lacks reference to a specific subcellular location. This is despite data over the years showing differences in the morphology and function of subsarcolemmal (found near the plasma membrane) and intermyofibrillar (nested between the myofibrils) mitochondria in skeletal muscle. Recent studies reveal that impairments in mitochondrial function in obesity with respect to the subcellular location of the mitochondria in muscle are more readily evident following exposure of the skeletal muscle to physiological stimuli. In this review, we highlight the need to understand skeletal muscle mitochondria metabolism in obesity in a subpopulation-specific manner and in the presence of physiological stimuli that modify mitochondrial function in vivo. Experimental approaches employed under these conditions will allow for more precise characterization of impairments in skeletal muscle mitochondria and their implications in inducing metabolic dysfunction in human obesity.

scholarly journals Comparison of in vivo postexercise phosphocreatine recovery and resting ATP synthesis flux for the assessment of skeletal muscle mitochondrial function

2010 ◽  
Vol 299 (5) ◽  
pp. C1136-C1143 ◽  
Author(s):  
N. M. A. van den Broek ◽  
J. Ciapaite ◽  
K. Nicolay ◽  
J. J. Prompers
Keyword(s):  
Skeletal Muscle ◽  
Oxygen Consumption ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Atp Synthesis ◽  
Resonance Spectroscopy ◽  
Isolated Mitochondria ◽  
Significant Difference

31P magnetic resonance spectroscopy (MRS) has been used to assess skeletal muscle mitochondrial function in vivo by measuring 1) phosphocreatine (PCr) recovery after exercise or 2) resting ATP synthesis flux with saturation transfer (ST). In this study, we compared both parameters in a rat model of mitochondrial dysfunction with the aim of establishing the most appropriate method for the assessment of in vivo muscle mitochondrial function. Mitochondrial dysfunction was induced in adult Wistar rats by daily subcutaneous injections with the complex I inhibitor diphenyleneiodonium (DPI) for 2 wk. In vivo 31P MRS measurements were supplemented by in vitro measurements of oxygen consumption in isolated mitochondria. Two weeks of DPI treatment induced mitochondrial dysfunction, as evidenced by a 20% lower maximal ADP-stimulated oxygen consumption rate in isolated mitochondria from DPI-treated rats oxidizing pyruvate plus malate. This was paralleled by a 46% decrease in in vivo oxidative capacity, determined from postexercise PCr recovery. Interestingly, no significant difference in resting, ST-based ATP synthesis flux was observed between DPI-treated rats and controls. These results show that PCr recovery after exercise has a more direct relationship with skeletal muscle mitochondrial function than the ATP synthesis flux measured with 31P ST MRS in the resting state.

scholarly journals Early or advanced stage type 2 diabetes is not accompanied by in vivo skeletal muscle mitochondrial dysfunction

2008 ◽  
Vol 158 (5) ◽  
pp. 643-653 ◽  
Author(s):  
H M De Feyter ◽  
N M A van den Broek ◽  
S F E Praet ◽  
K Nicolay ◽  
L J C van Loon ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Resonance Spectroscopy ◽  
Diabetes Patients

ObjectiveSeveral lines of evidence support a potential role of skeletal muscle mitochondrial dysfunction in the pathogenesis of insulin resistance and/or type 2 diabetes. However, it remains to be established whether mitochondrial dysfunction represents either cause or consequence of the disease. We examined in vivo skeletal muscle mitochondrial function in early and advanced stages of type 2 diabetes, with the aim to gain insight in the proposed role of mitochondrial dysfunction in the aetiology of insulin resistance and/or type 2 diabetes.MethodsTen long-standing, insulin-treated type 2 diabetes patients, 11 subjects with impaired fasting glucose, impaired glucose tolerance and/or recently diagnosed type 2 diabetes, and 12 healthy, normoglycaemic controls, matched for age and body composition and with low habitual physical activity levels were studied. In vivo mitochondrial function of the vastus lateralis muscle was evaluated from post-exercise phosphocreatine (PCr) recovery kinetics using 31P magnetic resonance spectroscopy (MRS). Intramyocellular lipid (IMCL) content was assessed in the same muscle using single-voxel 1H MRS.ResultsIMCL content tended to be higher in the type 2 diabetes patients when compared with normoglycaemic controls (P=0.06). The31P MRS parameters for mitochondrial function, i.e. PCr and ADP recovery time constants and maximum aerobic capacity, did not differ between groups.ConclusionsThe finding that in vivo skeletal muscle oxidative capacity does not differ between long-standing, insulin-treated type 2 diabetes patients, subjects with early stage type 2 diabetes and sedentary, normoglycaemic controls suggests that mitochondrial dysfunction does not necessarily represent either cause or consequence of insulin resistance and/or type 2 diabetes.

scholarly journals ApoE4 (Δ272–299) induces mitochondrial‐associated membrane formation and mitochondrial impairment by enhancing GRP75-modulated mitochondrial calcium overload in neuron

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tao Liang ◽  
Weijian Hang ◽  
Jiehui Chen ◽  
Yue Wu ◽  
Bin Wen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Calcium Transport ◽  
Calcium Overload ◽  
Mitochondrial Calcium ◽  
Mitochondrial Impairment

Abstract Background Apolipoprotein E4 (apoE4) is a major genetic risk factor of Alzheimer’s disease. Its C-terminal-truncated apoE4 (Δ272–299) has neurotoxicity by affecting mitochondrial respiratory function. However, the molecular mechanism(s) underlying the action of apoE4 (Δ272–299) in mitochondrial function remain poorly understood. Methods The impact of neuronal apoE4 (Δ272–299) expression on ER stress, mitochondrial-associated membrane (MAM) formation, GRP75, calcium transport and mitochondrial impairment was determined in vivo and in vitro. Furthermore, the importance of ER stress or GRP75 activity in the apoE4 (Δ272–299)-promoted mitochondrial dysfunction in neuron was investigated. Results Neuronal apoE4 (Δ272–299) expression induced mitochondrial impairment by inducing ER stress and mitochondrial-associated membrane (MAM) formation in vivo and in vitro. Furthermore, apoE4 (Δ272–299) expression promoted GRP75 expression, mitochondrial dysfunction and calcium transport into the mitochondria in neuron, which were significantly mitigated by treatment with PBA (an inhibitor of ER stress), MKT077 (a specific GRP75 inhibitor) or GRP75 silencing. Conclusions ApoE4 (Δ272–299) significantly impaired neuron mitochondrial function by triggering ER stress, up-regulating GRP75 expression to increase MAM formation, and mitochondrial calcium overload. Our findings may provide new insights into the neurotoxicity of apoE4 (Δ272–299) against mitochondrial function and uncover new therapeutic targets for the intervention of Alzheimer’s disease.

Vitamin E prevents hypobaric hypoxia-induced mitochondrial dysfunction in skeletal muscle

2007 ◽  
Vol 113 (12) ◽  
pp. 459-466 ◽  
Author(s):  
José Magalhães ◽  
Rita Ferreira ◽  
Maria J. Neuparth ◽  
Paulo J. Oliveira ◽  
Franklim Marques ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Vitamin E ◽  
Mitochondrial Dysfunction ◽  
Hypobaric Hypoxia ◽  
Mitochondrial Membrane ◽  
Mitochondrial Protein ◽  
Membrane Integrity ◽  
Outer Mitochondrial Membrane ◽  
Hypoxia Exposure

In the present study, the effect of vitamin E (α-tocopherol) on mice skeletal muscle mitochondrial dysfunction and oxidative damage induced by an in vivo acute and severe hypobaric hypoxic insult (48 h at a barometric pressure equivalent to 8500 m) has been investigated. Male mice (n=24) were randomly divided into the following four groups (n=6): control (C), hypoxia (H), vitamin E (VE; 60 mg/kg of body weight intraperitoneally, three times/week for 3 weeks) and hypoxia+VE (HVE). A significant increase in mitochondrial protein CGs (carbonyl groups) was found in the H group compared with the C group. Confirming previous observations from our group, hypoxia induced mitochondrial dysfunction, as identified by altered respiratory parameters. Hypoxia exposure increased Bax content and decreased the Bcl-2/Bax ratio, whereas Bcl-2 remained unchanged. Inner and outer mitochondrial membrane integrity were significantly affected by hypoxia exposure; however, vitamin E treatment attenuated the effect of hypoxia on mitochondrial oxidative phosphorylation and on the levels of CGs. Vitamin E supplementation also prevented the Bax and Bcl-2/Bax ratio impairments caused by hypoxia, as well as the decrease in inner and outer mitochondrial membrane integrity. In conclusion, the results suggest that vitamin E prevents the loss of mitochondrial integrity and function, as well as the increase in Bax content, which suggests that mitochondria are involved in increased cell death induced by severe hypobaric hypoxia in mice skeletal muscle.

Sign in / Sign up

Export Citation Format

Share Document