bims-misrem Biomed News
on Mitochondria and sarcoplasmic reticulum in muscle mass
Issue of 2021‒04‒18
ten papers selected by
Rafael Antonio Casuso Pérez
University of Granada

  1. J Endocrinol. 2021 May;pii: JOE-20-0233. [Epub ahead of print]249(2): 113-124
      Vitamin D deficiency is associated with symptoms of skeletal muscle myopathy including muscle weakness and fatigue. Recently, vitamin D-related metabolites have been linked to the maintenance of mitochondrial function within skeletal muscle. However, current evidence is limited to in vitro models and the effects of diet-induced vitamin D deficiency upon skeletal muscle mitochondrial function in vivo have received little attention. In order to examine the role of vitamin D in the maintenance of mitochondrial function in vivo, we utilised an established model of diet-induced vitamin D deficiency in C57BL/6J mice. Mice were either fed a control diet (2200 IU/kg i.e. vitamin D replete) or a vitamin D-deplete (0 IU/kg) diet for periods of 1, 2 and 3 months. Gastrocnemius muscle mitochondrial function and ADP sensitivity were assessed via high-resolution respirometry and mitochondrial protein content via immunoblotting. As a result of 3 months of diet-induced vitamin D deficiency, respiration supported via complex I + II (CI + IIP) and the electron transport chain (ETC) were 35 and 37% lower when compared to vitamin D-replete mice (P < 0.05). Despite functional alterations, citrate synthase activity, AMPK phosphorylation, mitofilin, OPA1 and ETC subunit protein content remained unchanged in response to dietary intervention (P > 0.05). In conclusion, we report that 3 months of diet-induced vitamin D deficiency reduced skeletal muscle mitochondrial respiration in C57BL/6J mice. Our data, when combined with previous in vitro observations, suggest that vitamin D-mediated regulation of mitochondrial function may underlie the exacerbated muscle fatigue and performance deficits observed during vitamin D deficiency.
    Keywords:  mitochondria; skeletal muscle; vitamin D
  2. Am J Physiol Endocrinol Metab. 2021 Apr 12.
      Ketogenic diets (KD) are reported to improve body weight, fat mass, and exercise performance in humans. Unfortunately, most rodent studies have used a low-protein KD, which does not recapitulate diets used by humans. Since skeletal muscle plays a critical role in responding to macronutrient perturbations induced by diet and exercise, the purpose of this study was to test if a normal-protein KD (NPKD) impacts shifts in skeletal muscle substrate oxidative capacity in response to exercise training (ExTr). A high fat, carbohydrate-deficient NPKD (16.1% protein, 83.9% fat, 0% carbohydrate) was given to C57BL/6J male mice for 6 weeks, while controls received a low fat diet with similar protein (15.9% protein, 11.9% fat, 72.2% carbohydrate). On week four of the diet, mice began treadmill training 5 days/week, 60 min/day for 3 weeks. NPKD-fed mice increased body weight and fat mass, while ExTr negated a continued rise in adiposity. ExTr increased intramuscular glycogen, while the NPKD increased intramuscular triglycerides. Neither the NPKD nor ExTr alone altered mitochondrial content; however, in combination, the NPKD-ExTr group showed increases in PGC-1α, as well as markers of mitochondrial fission and fusion. Pyruvate oxidative capacity was unchanged by either intervention, while ExTr increased leucine oxidation in NPKD-fed mice. Lipid metabolism pathways had the most notable changes as the NPKD and ExTr interventions both enhanced mitochondrial and peroxisomal lipid oxidation and many adaptations were additive or synergistic. Overall these results suggest a combination of a NPKD and ExTr induces additive and/or synergistic adaptations in skeletal muscle oxidative capacity.
    Keywords:  exercise; ketogenic diet; mitochondria; peroxisomal; substrate oxidation
  3. Sci Adv. 2021 Apr;pii: eabf2856. [Epub ahead of print]7(16):
      Exercise training is a powerful strategy to prevent and combat cardiovascular and metabolic diseases, although the integrative nature of the training-induced adaptations is not completely understood. We show that chronic blockade of histamine H1/H2 receptors led to marked impairments of microvascular and mitochondrial adaptations to interval training in humans. Consequently, functional adaptations in exercise capacity, whole-body glycemic control, and vascular function were blunted. Furthermore, the sustained elevation of muscle perfusion after acute interval exercise was severely reduced when H1/H2 receptors were pharmaceutically blocked. Our work suggests that histamine H1/H2 receptors are important transducers of the integrative exercise training response in humans, potentially related to regulation of optimal post-exercise muscle perfusion. These findings add to our understanding of how skeletal muscle and the cardiovascular system adapt to exercise training, knowledge that will help us further unravel and develop the exercise-is-medicine concept.
  4. Front Cell Dev Biol. 2021 ;9 626117
      Mammalian mitochondria are emerging as a critical stress-responsive contributor to cellular life/death and developmental outcomes. Maintained as an organellar network distributed throughout the cell, mitochondria respond to cellular stimuli and stresses through highly sensitive structural dynamics, particularly in energetically demanding cell settings such as cardiac and muscle tissues. Fusion allows individual mitochondria to form an interconnected reticular network, while fission divides the network into a collection of vesicular organelles. Crucially, optic atrophy-1 (OPA1) directly links mitochondrial structure and bioenergetic function: when the transmembrane potential across the inner membrane (ΔΨm) is intact, long L-OPA1 isoforms carry out fusion of the mitochondrial inner membrane. When ΔΨm is lost, L-OPA1 is cleaved to short, fusion-inactive S-OPA1 isoforms by the stress-sensitive OMA1 metalloprotease, causing the mitochondrial network to collapse to a fragmented population of organelles. This proteolytic mechanism provides sensitive regulation of organellar structure/function but also engages directly with apoptotic factors as a major mechanism of mitochondrial participation in cellular stress response. Furthermore, emerging evidence suggests that this proteolytic mechanism may have critical importance for cell developmental programs, particularly in cardiac, neuronal, and stem cell settings. OMA1's role as a key mitochondrial stress-sensitive protease motivates exciting new questions regarding its mechanistic regulation and interactions, as well as its broader importance through involvement in apoptotic, stress response, and developmental pathways.
    Keywords:  OMA1; OPA1; apoptosis; development; mitochondria
  5. Med Sci Sports Exerc. 2021 May 01. 53(5): 894-903
      PURPOSE: This study aimed to evaluate the influence of lifelong regular physical activity on skeletal muscle capillarization in women.METHODS: Postmenopausal women, 61±4 yr old, were divided according to self-reported physical activity level over the past 20 yrs: sedentary (SED; n = 14), moderately active (MOD; n = 12), and very active (VERY; n = 15). Leg blood flow (LBF) was determined by ultrasound Doppler, and blood samples were drawn from the femoral artery and vein for calculation of leg oxygen uptake (LVO2) at rest and during one-legged knee extensor exercise. A skeletal muscle biopsy was obtained from the vastus lateralis and analyzed for capillarization and vascular endothelial growth factor (VEGF) and mitochondrial OXPHOS proteins. Platelets were isolated from venous blood and analyzed for VEGF content and effect on endothelial cell proliferation.
    RESULTS: The exercise-induced rise in LBF and LVO2 was faster (P = 0.008) in VERY compared with SED and MOD. Steady-state LBF and LVO2 were lower (P < 0.04) in MOD and VERY compared with SED. Capillary-fiber ratio and capillary density were greater (P < 0.03) in VERY (1.65 ± 0.48 and 409.3 ± 57.5) compared with MOD (1.30 ± 0.19 and 365.0 ± 40.2) and SED (1.30 ± 0.30 and 356.2 ± 66.3). Skeletal muscle VEGF and OXPHOS complexes I, II, and V were ~1.6-fold and ~1.25-fold (P < 0.01) higher, respectively, in VERY compared with SED. Platelets from all groups induced an approximately nine-fold (P < 0.001) increase in endothelial cell proliferation.
    CONCLUSION: A very active lifestyle is associated with superior skeletal muscle exercise hemodynamics and greater potential for oxygen extraction concurrent with a higher skeletal muscle capillarization and mitochondrial capacity.
  6. J Mol Cell Cardiol. 2021 Apr 12. pii: S0022-2828(21)00078-X. [Epub ahead of print]
      Sudden cardiac death due to ventricular tachyarrhythmias remains the major cause of mortality in the world. Heart failure, diabetic cardiomyopathy, old age-related cardiac dysfunction and inherited disorders are associated with enhanced propensity to malignant cardiac arrhythmias. Both defective mitochondrial function and abnormal intracellular Ca2+ homeostasis have been established as the key contributing factors in the pathophysiology and arrhythmogenesis in these conditions. This article reviews current advances in understanding of bidirectional control of ryanodine receptor-mediated sarcoplasmic reticulum Ca2+ release and mitochondrial function, and how defects in crosstalk between these two organelles increase arrhythmic risk in cardiac disease.
    Keywords:  Calcium signaling; Cardiac arrhythmia; Mitochondria; Sarcoplasmic reticulum
  7. Redox Biol. 2021 Apr 05. pii: S2213-2317(21)00114-2. [Epub ahead of print]43 101966
      Skeletal muscle health is important for the prevention of various age-related diseases. The loss of skeletal muscle mass, which is known as sarcopenia, underlies physical disability, poor quality of life and chronic diseases in elderly people. The transcription factor NRF2 plays important roles in the regulation of the cellular defense against oxidative stress, as well as the metabolism and mitochondrial activity. To determine the contribution of skeletal muscle NRF2 to exercise capacity, we conducted skeletal muscle-specific inhibition of KEAP1, which is a negative regulator of NRF2, and examined the cell-autonomous and non-cell-autonomous effects of NRF2 pathway activation in skeletal muscles. We found that NRF2 activation in skeletal muscles increased slow oxidative muscle fiber type and improved exercise endurance capacity in female mice. We also observed that female mice with NRF2 pathway activation in their skeletal muscles exhibited enhanced exercise-induced mobilization and β-oxidation of fatty acids. These results indicate that NRF2 activation in skeletal muscles promotes communication with adipose tissues via humoral and/or neuronal signaling and facilitates the utilization of fatty acids as an energy source, resulting in increased mitochondrial activity and efficient energy production during exercise, which leads to improved exercise endurance.
    Keywords:  Beta-oxidation; Exercise; Fatty acid; KEAP1-NRF2 system; Skeletal muscle
  8. Circ Res. 2021 Apr 16. 128(8): 1205-1207
    Keywords:  Editorials; animal models; calcium; cardiac myocyte; heart failure; mitochondria
  9. Cell Rep. 2021 Apr 13. pii: S2211-1247(21)00261-8. [Epub ahead of print]35(2): 108947
      During mitochondrial fission, key molecular and cellular factors assemble on the outer mitochondrial membrane, where they coordinate to generate constriction. Constriction sites can eventually divide or reverse upon disassembly of the machinery. However, a role for membrane tension in mitochondrial fission, although speculated, has remained undefined. We capture the dynamics of constricting mitochondria in mammalian cells using live-cell structured illumination microscopy (SIM). By analyzing the diameters of tubules that emerge from mitochondria and implementing a fluorescence lifetime-based mitochondrial membrane tension sensor, we discover that mitochondria are indeed under tension. Under perturbations that reduce mitochondrial tension, constrictions initiate at the same rate, but are less likely to divide. We propose a model based on our estimates of mitochondrial membrane tension and bending energy in living cells which accounts for the observed probability distribution for mitochondrial constrictions to divide.
    Keywords:  fluorescence lifetime; fluorescent tension sensor; membrane tension; microtubules; mitochondrial division; mitochondrial dynamics; super-resolution microscopy
  10. Curr Obes Rep. 2021 Apr 10.
      PURPOSE OF REVIEW: The term "metabolic flexibility" denotes the dynamic responses of the cellular oxidative machinery in order to adapt to changes in energy substrate availability. A progressive loss of this adaptive capacity has been implicated in the development of obesity-related comorbidities. Mitochondria are dynamic intracellular organelles which play a fundamental role in energy metabolism, and the mitochondrial adaptation to environmental challenges may be viewed as the functional component of metabolic flexibility. Herein, we attempt to comprehensively review the available evidence regarding the role of mitochondrial adaptation and metabolic flexibility in the pathogenesis of obesity and related morbidities, namely insulin resistance states and non-alcoholic fatty liver disease (NAFLD).RECENT FINDINGS: Overall, there is a concrete body of evidence to support the presence of impaired mitochondrial adaptation as a principal component of systemic metabolic inflexibility in conditions related to obesity. There are still many unresolved questions regarding the relationship between the gradual loss of mitochondrial adaptability and the progression of obesity-related complications, such as causality issues, the timely appearance and reversibility of the described disturbances, and the generalizability of the findings to the mitochondrial content of every affected tissue or organ. The evidence regarding the causality between the observed associations remains inconclusive, although most of the available data points towards a bidirectional, potentially mutually amplifying relationship. The spectrum of NAFLD is of particular interest, since functional and pathological changes in the course of its development closely mirror the progression of dysmetabolism, if not constituting a dynamic component of the latter.
    Keywords:  Diabetes mellitus; Insulin resistance; Metabolic flexibility; Mitochondrial adaptation; NAFLD; Obesity; Plasticity