bims-misrem 2021-08-08 papers

Nat Commun. 2021 Aug 06. 12(1): 4773

Impact of aging and exercise on skeletal muscle mitochondrial capacity, energy metabolism, and physical function.

L Grevendonk, N J Connell, C McCrum, C E Fealy, L Bilet, Y M H Bruls, J Mevenkamp, V B Schrauwen-Hinderling, J A Jörgensen, E Moonen-Kornips, G Schaart, B Havekes, J de Vogel-van den Bosch, M C E Bragt, K Meijer, P Schrauwen, J Hoeks.

The relationship between the age-associated decline in mitochondrial function and its effect on skeletal muscle physiology and function remain unclear. In the current study, we examined to what extent physical activity contributes to the decline in mitochondrial function and muscle health during aging and compared mitochondrial function in young and older adults, with similar habitual physical activity levels. We also studied exercise-trained older adults and physically impaired older adults. Aging was associated with a decline in mitochondrial capacity, exercise capacity and efficiency, gait stability, muscle function, and insulin sensitivity, even when maintaining an adequate daily physical activity level. Our data also suggest that a further increase in physical activity level, achieved through regular exercise training, can largely negate the effects of aging. Finally, mitochondrial capacity correlated with exercise efficiency and insulin sensitivity. Together, our data support a link between mitochondrial function and age-associated deterioration of skeletal muscle.

DOI: https://doi.org/10.1038/s41467-021-24956-2

Mol Cell. 2021 Jul 27. pii: S1097-2765(21)00583-9. [Epub ahead of print]

Oxidative bursts of single mitochondria mediate retrograde signaling toward the ER.

David M Booth, Péter Várnai, Suresh K Joseph, György Hajnóczky.

The emerging role of mitochondria as signaling organelles raises the question of whether individual mitochondria can initiate heterotypic communication with neighboring organelles. Using fluorescent probes targeted to the endoplasmic-reticulum-mitochondrial interface, we demonstrate that single mitochondria generate oxidative bursts, rapid redox oscillations, confined to the nanoscale environment of the interorganellar contact sites. Using probes fused to inositol 1,4,5-trisphosphate receptors (IP3Rs), we show that Ca2+ channels directly sense oxidative bursts and respond with Ca2+ transients adjacent to active mitochondria. Application of specific mitochondrial stressors or apoptotic stimuli dramatically increases the frequency and amplitude of the oxidative bursts by enhancing transient permeability transition pore openings. Conversely, blocking interface Ca2+ transport via elimination of IP3Rs or mitochondrial calcium uniporter channels suppresses ER-mitochondrial Ca2+ feedback and cell death. Thus, single mitochondria initiate local retrograde signaling by miniature oxidative bursts and, upon metabolic or apoptotic stress, may also amplify signals to the rest of the cell.

Keywords: Ca2+ microdomain; Inositol-1,4,5-trisphosphate receptor; Mitochondrial retrograde signaling; Organelle contacts; Redox nanodomain

DOI: https://doi.org/10.1016/j.molcel.2021.07.014

FASEB J. 2021 Sep;35(9): e21830

Transcriptomic links to muscle mass loss and declines in cumulative muscle protein synthesis during short-term disuse in healthy younger humans.

Craig R G Willis, Iain J Gallagher, Daniel J Wilkinson, Matthew S Brook, Joseph J Bass, Bethan E Phillips, Kenneth Smith, Timothy Etheridge, Tanner Stokes, Chris McGlory, Stefan H M Gorissen, Nathaniel J Szewczyk, Stuart M Phillips, Philip J Atherton.

Muscle disuse leads to a rapid decline in muscle mass, with reduced muscle protein synthesis (MPS) considered the primary physiological mechanism. Here, we employed a systems biology approach to uncover molecular networks and key molecular candidates that quantitatively link to the degree of muscle atrophy and/or extent of decline in MPS during short-term disuse in humans. After consuming a bolus dose of deuterium oxide (D2 O; 3 mL.kg-1 ), eight healthy males (22 ± 2 years) underwent 4 days of unilateral lower-limb immobilization. Bilateral muscle biopsies were obtained post-intervention for RNA sequencing and D2 O-derived measurement of MPS, with thigh lean mass quantified using dual-energy X-ray absorptiometry. Application of weighted gene co-expression network analysis identified 15 distinct gene clusters ("modules") with an expression profile regulated by disuse and/or quantitatively connected to disuse-induced muscle mass or MPS changes. Module scans for candidate targets established an experimentally tractable set of candidate regulatory molecules (242 hub genes, 31 transcriptional regulators) associated with disuse-induced maladaptation, many themselves potently tied to disuse-induced reductions in muscle mass and/or MPS and, therefore, strong physiologically relevant candidates. Notably, we implicate a putative role for muscle protein breakdown-related molecular networks in impairing MPS during short-term disuse, and further establish DEPTOR (a potent mTOR inhibitor) as a critical mechanistic candidate of disuse driven MPS suppression in humans. Overall, these findings offer a strong benchmark for accelerating mechanistic understanding of short-term muscle disuse atrophy that may help expedite development of therapeutic interventions.

Keywords: atrophy; disuse; gene network analysis; muscle protein synthesis; skeletal muscle

DOI: https://doi.org/10.1096/fj.202100276RR

Biochem Soc Trans. 2021 Aug 02. pii: BST20210496. [Epub ahead of print]

Are cachexia-associated tumors transmitTERS of ER stress?

Ana Sayuri Yamagata, Paula Paccielli Freire.

Cancer cachexia is associated with deficient response to chemotherapy. On the other hand, the tumors of cachectic patients remarkably express more chemokines and have higher immune infiltration. For immunogenicity, a strong induction of the unfolded protein response (UPR) is necessary. UPR followed by cell surface exposure of calreticulin on the dying tumor cell is essential for its engulfment by macrophages and dendritic cells. However, some tumor cells upon endoplasmic reticulum (ER) stress can release factors that induce ER stress to other cells, in the so-called transmissible ER stress (TERS). The cells that received TERS produce more interleukin 6 (IL-6) and chemokines and acquire resistance to subsequent ER stress, nutrient deprivation, and genotoxic stress. Since ER stress enhances the release of extracellular vesicles (EVs), we suggest they can mediate TERS. It was found that ER stressed cachexia-inducing tumor cells transmit factors that trigger ER stress in other cells. Therefore, considering the role of EVs in cancer cachexia, the release of exosomes can possibly play a role in the process of blunting the immunogenicity of the cachexia-associated tumors. We propose that TERS can cause an inflammatory and immunosuppressive phenotype in cachexia-inducing tumors.

Keywords: ER stress; cachexia; cancer; immunology; tumor microenvironment

DOI: https://doi.org/10.1042/BST20210496