bims-misrem Biomed News
on Mitochondria and sarcoplasmic reticulum in muscle mass
Issue of 2020‒10‒18
six papers selected by
Rafael Antonio Casuso Pérez
University of Granada


  1. Mech Ageing Dev. 2020 Oct 09. pii: S0047-6374(20)30176-7. [Epub ahead of print] 111380
    Thompson J, Maceyka M, Chen Q.
      Severity of cardiovascular disease increases markedly in elderly patients. In addition, many therapeutic strategies that decrease cardiac injury in adult patients are invalid in elderly patients. Thus, it is a challenge to protect the aged heart in the context of underlying chronic or acute cardiac diseases including ischemia-reperfusion injury. The cause(s) of this age-related increased damage remain unknown. Aging impairs the function of the mitochondrial electron transport chain (ETC), leading to decreased energy production and increased oxidative stress due to generation of reactive oxygen species (ROS). Additionally, ROS-induced oxidative stress can increase cardiac injury during ischemia-reperfusion by potentiating mitochondrial permeability transition pore (MPTP) opening. Aging leads to increased endoplasmic reticulum (ER) stress, which contributes to mitochondrial dysfunction, including reduced function of the ETC. The activation of both cytosolic and mitochondrial calcium-activated proteases termed calpains leads to mitochondrial dysfunction and decreased ETC function. Intriguingly, mitochondrial ROS generation also induces ER stress, highlighting the dynamic interaction between mitochondria and ER. Here, we discuss the role of ER stress in sensitizing and potentiating mitochondrial dysfunction in response to ischemia-reperfusion, and the promising potential therapeutic benefit of inhibition of ER stress and / or calpains to attenuate cardiac injury in elderly patients.
    Keywords:  Aging; Calpain; ER stress; Ischemia-reperfusion; Mitochondria
    DOI:  https://doi.org/10.1016/j.mad.2020.111380
  2. Physiol Rep. 2020 Oct;8(19): e14575
    Wu H, Jang J, Dridi S, Ferrando AA, Wolfe RR, Kim IY, Baum JI.
      The mechanisms leading to sarcopenia, the main cause for frailty in older adults, are still unclear. Autophagy and the ubiquitin-proteasome system (UPS) may play a role in mediating muscle protein breakdown related to sarcopenia. In addition to loss of muscle mass, compromised muscle performance observed in sarcopenic patients has been linked to muscle mitochondria dysfunction. Increased fat deposition and fat cell infiltration in muscle frequently seen in skeletal muscle of older adults may play an additional role for the pathogenesis of sarcopenia. Therefore, the first objective of this study was to understand differences in expression of genes related to autophagy, UPS, mitochondrial biogenesis, and fat metabolism in skeletal muscle of older adults compared with young adults. Our second objective was to determine the correlation between whole body protein kinetics (WBPK) and gene expression with age. Real-time quantitative PCR was used to determine the relative expression of targeted genes, and hierarchical regression analysis was used to determine if age had a moderating effect on the correlation between expression of targeted genes and WBPK. Increases in the expression of autophagy-related genes and fat metabolism-related genes were observed in muscle of older adults compared with young adults. In addition, age enhanced the negative correlations between mitochondrial biogenesis genes and net protein balance. These results suggest that dysregulated gene expression of mitochondrial biogenesis could play a role in muscle loss in older adults.
    Keywords:  autophagy; muscle; protein breakdown; protein synthesis; sarcopenia
    DOI:  https://doi.org/10.14814/phy2.14575
  3. Front Aging Neurosci. 2020 ;12 581849
    Muñoz-Carvajal F, Sanhueza M.
      Aging is the time-dependent functional decline that increases the vulnerability to different forms of stress, constituting the major risk factor for the development of neurodegenerative diseases. Dysfunctional mitochondria significantly contribute to aging phenotypes, accumulating particularly in post-mitotic cells, including neurons. To cope with deleterious effects, mitochondria feature different mechanisms for quality control. One such mechanism is the mitochondrial unfolded protein response (UPRMT), which corresponds to the transcriptional activation of mitochondrial chaperones, proteases, and antioxidant enzymes to repair defective mitochondria. Transcription of target UPRMT genes is epigenetically regulated by Histone 3-specific methylation. Age-dependency of this regulation could explain a differential UPRMT activity in early developmental stages or aged organisms. At the same time, precise tuning of mitochondrial stress responses is crucial for maintaining neuronal homeostasis. However, compared to other mitochondrial and stress response programs, the role of UPRMT in neurodegenerative disease is barely understood and studies in this topic are just emerging. In this review, we document the reported evidence characterizing the evolutionarily conserved regulation of the UPRMT and summarize the recent advances in understanding the role of the pathway in neurodegenerative diseases and aging.
    Keywords:  aging; epigenetic regulation; mitochondria; mitochondrial unfolded protein response; neurodegenerative diseases; stress response
    DOI:  https://doi.org/10.3389/fnagi.2020.581849
  4. FASEB J. 2020 Oct 08.
    Endo Y, Baldino K, Li B, Zhang Y, Sakthivel D, MacArthur M, Panayi AC, Kip P, Spencer DJ, Jasuja R, Bagchi D, Bhasin S, Nuutila K, Neppl RL, Wagers AJ, Sinha I.
      The ability of skeletal muscle to regenerate declines significantly with aging. The expression of aryl hydrocarbon receptor nuclear translocator (ARNT), a critical component of the hypoxia signaling pathway, was less abundant in skeletal muscle of old (23-25 months old) mice. This loss of ARNT was associated with decreased levels of Notch1 intracellular domain (N1ICD) and impaired regenerative response to injury in comparison to young (2-3 months old) mice. Knockdown of ARNT in a primary muscle cell line impaired differentiation in vitro. Skeletal muscle-specific ARNT deletion in young mice resulted in decreased levels of whole muscle N1ICD and limited muscle regeneration. Administration of a systemic hypoxia pathway activator (ML228), which simulates the actions of ARNT, rescued skeletal muscle regeneration in both old and ARNT-deleted mice. These results suggest that the loss of ARNT in skeletal muscle is partially responsible for diminished myogenic potential in aging and activation of hypoxia signaling holds promise for rescuing regenerative activity in old muscle.
    Keywords:  aging; hypoxia signaling; muscle regeneration
    DOI:  https://doi.org/10.1096/fj.202000761RR
  5. J Appl Physiol (1985). 2020 Oct 15.
    Lavin KM, Perkins RK, Jemiolo B, Raue U, Trappe SW, Trappe TA.
      Low muscle mass and frailty are especially prevalent in older women and may be accelerated by age-related inflammation. Habitual physical activity throughout the lifespan (lifelong exercise) may prevent muscle inflammation and associated pathologies, but this is unexplored in women. This investigation assessed basal and acute exercise-induced inflammation in three cohorts of women: young exercisers (YE, n=10, 25±1y, VO2max:44±2mL/kg/min, quadriceps size:59±2cm2), old healthy non-exercisers (OH, n=10, 75±1y, VO2max:18±1mL/kg/min, quadriceps size:40±1cm2), and lifelong aerobic exercisers with a 48±2y aerobic training history (LLE, n=7, 72±2y, VO2max:26±2mL/kg/min, quadriceps size:42±2cm2). Resting serum IL-6, TNF-α, CRP, and IGF-1 were measured. Vastus lateralis muscle biopsies were obtained at rest (basal) and 4h after an acute exercise challenge (3x10reps, 70%1RM) to assess gene expression of cytokines (IL-6, TNF-α, IL-1β, IL-10, IL-4, IL-1Ra, TGF-β), chemokines (IL-8, MCP-1), cyclooxygenase enzymes (COX-1, COX-2), prostaglandin E2 synthases (mPGES-1, cPGES) and receptors (EP3-4), and macrophage markers (CD16b, CD163), as well as basal macrophage abundance (CD68+ cells). The older cohorts (LLE+OH combined) demonstrated higher muscle IL-6 and COX-1 (P≤0.05) than YE, while LLE expressed lower muscle IL-1β (P≤0.05 vs. OH). Acute exercise increased muscle IL-6 expression in YE only, whereas the older cohorts combined had higher postexercise expression of IL-8 and TNF-α (P≤0.05 vs. YE). Only LLE had increased postexercise expression of muscle IL-1β and MCP-1 (P≤0.05 vs. preexercise). Thus, aging in women led to mild basal and exercise-induced inflammation that was unaffected by lifelong aerobic exercise, which may have implications for long-term function and adaptability.
    Keywords:  acute exercise; inflammaging; inflammation; lifelong exercise; skeletal muscle
    DOI:  https://doi.org/10.1152/japplphysiol.00655.2020
  6. J Cell Biol. 2020 Nov 02. pii: e202003024. [Epub ahead of print]219(11):
    Tirrell PS, Nguyen KN, Luby-Phelps K, Friedman JR.
      MICOS is a conserved multisubunit complex that localizes to mitochondrial cristae junctions and organizes cristae positioning within the organelle. MICOS is organized into two independent subcomplexes; however, the mechanisms that dictate the assembly and spatial positioning of each MICOS subcomplex are poorly understood. Here, we determine that MICOS subcomplexes target independently of one another to sites on the inner mitochondrial membrane that are in proximity to contact sites between mitochondria and the ER. One subcomplex, composed of Mic27/Mic26/Mic10/Mic12, requires ERMES complex function for its assembly. In contrast, the principal MICOS component, Mic60, self-assembles and localizes in close proximity to the ER through an independent mechanism. We also find that Mic60 can uniquely redistribute adjacent to forced mitochondria-vacuole contact sites. Our data suggest that nonoverlapping properties of interorganelle contact sites provide spatial cues that enable MICOS assembly and ultimately lead to proper physical and functional organization of mitochondria.
    DOI:  https://doi.org/10.1083/jcb.202003024