bims-misrem Biomed News
on Mitochondria and sarcoplasmic reticulum in muscle mass
Issue of 2020‒12‒13
four papers selected by
Rafael Antonio Casuso Pérez
University of Granada

  1. Science. 2020 Dec 10. pii: eabc8059. [Epub ahead of print]
      Treatments are lacking for sarcopenia, a debilitating age-related skeletal muscle wasting syndrome. Here we identify elevated 15-PGDH, the Prostaglandin E2 (PGE2)-degrading enzyme, as a hallmark of aged tissues, including skeletal muscle. The resulting reduction in PGE2 signaling is a major contributor to muscle atrophy in aged mice and results from 15-PGDH-expressing myofibers and interstitial cells within muscle. Inhibition of 15-PGDH, by targeted genetic knockdown or a small molecule inhibitor, increases aged muscle mass, strength, and exercise performance. These physiological benefits arise from rejuvenated PGE2 levels which augment mitochondrial function and autophagy and decrease TGF-beta and ubiquitin-proteasome pathways. Our studies demonstrate a previously unrecognized role for PGE2 signaling in countering muscle atrophy and identify 15-PGDH as a promising therapeutic target to counter sarcopenia.
  2. Redox Biol. 2020 Nov 25. pii: S2213-2317(20)31007-7. [Epub ahead of print]38 101802
      Mechanical ventilation (MV) is a life-saving intervention for many critically ill patients. Unfortunately, an unintended consequence of prolonged MV is the rapid development of diaphragmatic atrophy and contractile dysfunction, known as ventilator-induced diaphragm dysfunction (VIDD). Although the mechanism(s) responsible for VIDD are not fully understood, abundant evidence reveals that oxidative stress leading to the activation of the major proteolytic systems (i.e., autophagy, ubiquitin-proteasome, caspase, and calpain) plays a dominant role. Of the proteolytic systems involved in VIDD, calpain has received limited experimental attention due to the longstanding dogma that calpain plays a minor role in inactivity-induced muscle atrophy. Guided by preliminary experiments, we tested the hypothesis that activation of calpains play an essential role in MV-induced oxidative stress and the development of VIDD. This premise was rigorously tested by transgene overexpression of calpastatin, an endogenous inhibitor of calpains. Animals with/without transfection of the calpastatin gene in diaphragm muscle fibers were exposed to 12 h of MV. Results confirmed that overexpression of calpastatin barred MV-induced activation of calpain in diaphragm fibers. Importantly, deterrence of calpain activation protected the diaphragm against MV-induced oxidative stress, fiber atrophy, and contractile dysfunction. Moreover, prevention of calpain activation in the diaphragm forstalled MV-induced mitochondrial dysfunction and prevented MV-induced activation of caspase-3 along with the transcription of muscle specific E3 ligases. Collectively, these results support the hypothesis that calpain activation plays an essential role in the early development of VIDD. Further, these findings provide the first direct evidence that calpain plays an important function in inactivity-induced mitochondrial dysfunction and oxidative stress in skeletal muscle fibers.
    Keywords:  Calpain; Calpastatin; Muscle atrophy; Muscle disuse; Muscle wasting; Oxidative stress
  3. Am J Physiol Cell Physiol. 2020 Dec 09.
      Calcium (Ca2+) signaling is critical for cell function and cell survival. Mitochondria play a major role in regulating the intracellular Ca2+ concentration ([Ca2+]i). Mitochondrial Ca2+ uptake is an important determinant of cell fate and governs respiration, mitophagy/autophagy, and mitochondrial pathway of apoptosis. Mitochondrial Ca2+ uptake occurs via the mitochondrial Ca2+ uniporter (MCU) complex. This review summarizes the current knowledge on the function of MCU complex, regulation of MCU channel, and the role of MCU in Ca2+ homeostasis and human disease pathogenesis. The channel core consists of four MCU subunits and EMRE. Regulatory proteins that interact with them include mitochondrial Ca2+ uptake 1/2 (MICU1/2), MCU dominant negative beta subunit (MCUb), MCU regu-lator 1 (MCUR1) and solute carrier 25A23 (SLC25A23). In addition to these proteins, cardiolipin, a mito-chondrial mem-brane-specific phospholipid, has been shown to interact with the channel core. The dynamic interplay between the core and regu-latory proteins modulates MCU channel activity after sensing local changes in [Ca2+]i, reactive oxygen species, and other environmental factors. Here, we highlight the structural details of the human MCU heteromeric assemblies and their known roles in regulating mitochondrial Ca2+ homeostasis. MCU dysfunction has been shown to alter mitochondrial Ca2+ dynamics, in turn eliciting cell apoptosis. Changes in mitochondrial Ca2+ uptake have been implicated in pathological con-ditions af-fecting multiple organs, including the heart, skeletal muscle, and brain. However, our structural and functional knowledge of this vital protein complex remains incomplete and under-standing the precise role for MCU-mediated mito-chondrial Ca2+ signaling in disease requires further research ef-forts.
    Keywords:  Calcium; Channel; MCU; mitochondria; uniporter
  4. Elife. 2020 Dec 09. pii: e62601. [Epub ahead of print]9
      The metazoan endoplasmic reticulum (ER) serves both as a hub for maturation of secreted proteins and as an intracellular calcium storage compartment, facilitating calcium release-dependent cellular processes. ER calcium depletion robustly activates the unfolded protein response (UPR). However, it is unclear how fluctuations in ER calcium impact organellar proteostasis. Here we report that calcium selectively affects the dynamics of the abundant metazoan ER Hsp70 chaperone BiP, by enhancing its affinity for ADP. In the calcium-replete ER, ADP rebinding to post-ATP hydrolysis BiP-substrate complexes competes with ATP binding during both spontaneous and co-chaperone-assisted nucleotide exchange, favouring substrate retention. Conversely, in the calcium-depleted ER, relative acceleration of ADP-to-ATP exchange favours substrate release. These findings explain the rapid dissociation of certain substrates from BiP observed in the calcium-depleted ER and suggest a mechanism for tuning ER quality control and coupling UPR activity to signals that mobilise ER calcium in secretory cells.
    Keywords:  biochemistry; cell biology; chemical biology; none