bims-misrem Biomed News
on Mitochondria and sarcoplasmic reticulum in muscle mass
Issue of 2020‒10‒04
six papers selected by
Rafael Antonio Casuso Pérez
University of Granada

  1. PLoS One. 2020 ;15(10): e0237138
      In Duchenne muscular dystrophy, a lack of dystrophin leads to extensive muscle weakness and atrophy that is linked to cellular metabolic dysfunction and oxidative stress. This dystrophinopathy results in a loss of tethering between microtubules and the sarcolemma. Microtubules are also believed to regulate mitochondrial bioenergetics potentially by binding the outer mitochondrial membrane voltage dependent anion channel (VDAC) and influencing permeability to ADP/ATP cycling. The objective of this investigation was to determine if a lack of dystrophin causes microtubule disorganization concurrent with mitochondrial dysfunction in skeletal muscle, and whether this relationship is linked to altered binding of tubulin to VDAC. In extensor digitorum longus (EDL) muscle from 4-week old D2.mdx mice, microtubule disorganization was observed when probing for α-tubulin. This cytoskeletal disorder was associated with a reduced ability of ADP to stimulate respiration and attenuate H2O2 emission relative to wildtype controls. However, this was not associated with altered α-tubulin-VDAC2 interactions. These findings reveal that microtubule disorganization in dystrophin-deficient EDL is associated with impaired ADP control of mitochondrial bioenergetics, and suggests that mechanisms alternative to α-tubulin's regulation of VDAC2 should be examined to understand how cytoskeletal disruption in the absence of dystrophin may cause metabolic dysfunctions in skeletal muscle.
  2. Am J Physiol Endocrinol Metab. 2020 Sep 28.
      Obesity and insulin resistance (IR) are associated with endoplasmic reticulum (ER) stress and mitochondrial dysfunction in several tissues. Although for many years mitochondrial and ER function were studied separately, these organelles also connect to produce interdependent functions. Communication occurs at mitochondria-associated ER membranes (MAM) and regulates lipid and calcium homeostasis, apoptosis, and the exchange of adenine nucleotides, among other things. Recent evidence suggests that MAMs contribute to organelle, cellular, and systemic metabolism. In obesity and IR models, metabolic tissues such as the liver, skeletal muscle, pancreas, and adipose tissue present alterations in MAM structure or function. The purpose of this mini-review is to highlight the MAM disruptions that occur in each tissue during obesity and IR and its relationship with glucose homeostasis and IR. We also discuss the current controversy that surrounds MAMs' role in the development of insulin resistance.
    Keywords:  MAMs; endoplasmic reticulum; glucose metabolism; insulin resistance; mitochondria
  3. Am J Physiol Endocrinol Metab. 2020 Sep 28.
      Animal data indicate that ketogenic diets are associated with improved mitochondrial function, but human data are lacking. We aimed to characterize skeletal muscle mitochondrial changes in response to a ketogenic diet combined with exercise training in healthy individuals. Twenty-nine physically active adults completed a 12-week supervised exercise program after self-selection into a ketogenic diet (KD, n=15) group or maintenance of their habitual mixed diet (MD, n=14). Measures of metabolic health and muscle biopsies (Vastus lateralis) were obtained before and after the intervention. Mitochondria were isolated from muscle and studied after exposure to carbohydrate (pyruvate), fat (palmitoyl-L-carnitine), and ketone (β-hydroxybutyrate+acetoacetate) substrates. Compared to MD, the KD resulted in increased whole-body resting fat oxidation (p<0.001) and decreased fasting insulin (p=0.019), insulin resistance (HOMA-IR, p=0.022), and visceral fat (p<0.001). The KD altered mitochondrial function as evidenced by increases in mitochondrial respiratory control ratio (19%, p=0.009), ATP production (36%, p=0.028), and ATP/H2O2 (36%, p=0.033) with the fat-based substrate. ATP production with the ketone-based substrate was 4 to 8 times lower than with other substrates, indicating minimal oxidation. The KD resulted in a small decrease in muscle glycogen (14%, p=0.035) and an increase in muscle triglyceride (81%, p=0.006). These results expand our understanding of human adaptation to a ketogenic diet combined with exercise. In conjunction with weight loss, we observed altered skeletal muscle mitochondrial function and efficiency, an effect that may contribute to the therapeutic use of ketogenic diets in various clinical conditions, especially those associated with insulin resistance.
    Keywords:  exercise; fat oxidation; ketogenic diet; mitochondria; skeletal muscle
  4. Biochim Biophys Acta Mol Basis Dis. 2020 Sep 28. pii: S0925-4439(20)30332-X. [Epub ahead of print] 165984
      Diabetes mellitus-induced heart disease, including diabetic cardiomyopathy, is an important medical problem and is difficult to treat. Diabetes mellitus increases the risk for heart failure and decreases cardiac myocyte function, which are linked to changes in cardiac mitochondrial energy metabolism. The free mitochondrial calcium concentration ([Ca2+]m) is fundamental in activating the mitochondrial respiratory chain complexes and ATP production and is also known to regulate the activity of key mitochondrial dehydrogenases. The mitochondrial calcium uniporter complex (MCUC) plays a major role in mediating mitochondrial Ca2+ import, and its expression and function therefore may have a marked impact on cardiac myocyte metabolism and function. Here, we summarize the pathophysiological role of [Ca2+]m handling and MCUC in the diabetic heart. In addition, we evaluate potential therapeutic targets, directed to the machinery that regulates mitochondrial calcium handling, to alleviated diabetes-related cardiac disease.
    Keywords:  Mitochondrial calcium uptake and release; cardiac myocytes; diabetic cardiomyopathy; mitochondrial calcium; therapeutic target
  5. Ageing Res Rev. 2020 Sep 26. pii: S1568-1637(20)30320-2. [Epub ahead of print] 101185
      BACKGROUND: Chronic inflammation has been associated with sarcopenia and its components skeletal muscle strength and muscle mass. The aim of this systematic review and meta-analysis was to determine the relationship between systemic inflammation, muscle strength and/or muscle mass in adults.METHODS: An electronic search using keywords such as 'acute phase proteins, cytokines and sarcopenia, muscle mass, muscle strength' was conducted via Pubmed, Web of Science and Embase from inception until the 30th of June 2020. A meta-analysis using correlation data was performed to determine the overall relationship between inflammation and muscle strength and muscle mass in adults.
    RESULTS: Overall, 168 articles; 149 cross-sectional articles (n = 76,899 participants, 47.0% male) and 19 longitudinal articles (n = 12,295 participants, 31.9% male) met inclusion criteria. Independent of disease state, higher levels of C reactive protein (CRP), Interleukin (IL)-6 and Tumor necrosis factor (TNF)α were associated with lower handgrip and knee extension strength (CRP; r = - 0.10, p < 0.001, IL-6; r = - 0.13, p < 0.001, TNFα; r = - 0.08, p < 0.001 and CRP; r = - 0.18, p < 0.001, IL-6; r = - 0.11, p < 0.001, TNFα; r = - 0.13, p < 0.001 respectively) and muscle mass (CRP; r = - 0.12, p < 0.001, IL-6; r = - 0.09, p < 0.001, TNFα; r = - 0.15, p < 0.001). Furthermore, higher levels of systemic inflammatory markers appeared to be associated with lower muscle strength and muscle mass over time.
    CONCLUSION: Higher levels of circulating inflammatory markers are significantly associated with lower skeletal muscle strength and muscle mass.
    Keywords:  C-Reactive Protein; Cytokines; Inflammation; Interleukin-6; Muscle Atrophy; Muscle Mass; Muscle Strength; Sarcopenia
  6. Clin Transl Med. 2020 Sep;10(5): e166
      BACKGROUND: Myocardial ischemia/reperfusion (MI/R) injury imposes devastating cardiovascular sequelae in particular cardiac dysfunction as a result of restored blood flow. However, the mechanism behind MI/R injury remains elusive. Mitochondrial ubiquitin ligase (MITOL/MARCH5) is localized at the mitochondria-ER contact site and may be activated in response to a variety of pathophysiological processes, such as apoptosis, mitochondrial injury, ER stress, hypoxia, and reactive oxygen species (ROS) generation. Irisin as a cleaved product of fibronectin type III domain-containing protein 5 (FNDC5) displays cardioprotection in diverse cardiac diseases.METHODS: This study was designed to examine the role of irisin and MITOL in MI/R injury. Male C57BL/6J mice (8-10-week-old) were administered adenovirus MITOL shRNA through intracardiac injection followed by MI/R surgery through ligation and release the slipknot of cardiac left anterior descending coronary artery.
    RESULTS: Our results showed that irisin improved myocardial function in the face of MI/R injury as evidenced by reduced myocardial infarct size, apoptotic rate, serum lactate dehydrogenase (LDH), ROS generation, and malondialdehyde (MDA) levels as well as lessened ER stress injury. Moreover, our results indicated that protective role of irisin was mediated by upregulation of MITOL. Irisin also protected H9c2 cells against simulated I/R through negating ER stress, apoptosis, ROS and MDA levels, as well as facilitating superoxide dismutase (SOD) by way of elevated MITOL expression.
    CONCLUSIONS: To this end, our data favored that irisin pretreatment protects against MI/R injury, ER stress, ROS production, and mitochondrial homeostasis through upregulation of MITOL. These findings depicted the therapeutic potential of irisin and MITOL in the management of MI/R injury in patients with ST-segment elevation.
    Keywords:  apoptosis; endoplasmic reticulum stress; irisin (FNDC5); mitochondrial ubiquitin ligase (MITOL); myocardial ischemia/reperfusion (MI/R); reactive oxygen species (ROS)