bims-misrem 2021-11-07 papers

J Appl Physiol (1985). 2021 Nov 04.

Short-term step reduction reduces CS activity without altering skeletal muscle markers of oxidative metabolism or insulin-mediated signalling in young males.

Sophie J Edwards, Brandon J Shad, Ryan N Marshall, Paul T Morgan, Gareth Anthony Wallis, Leigh Breen.

BACKGROUND: Mitochondria are critical to skeletal muscle contractile function and metabolic health. Short-term periods of step-reduction (SR) are associated with alterations in muscle protein turnover and mass. However, the effects of SR on mitochondrial metabolism/muscle oxidative metabolism and insulin-mediated signalling are unclear.
AIM: We tested the hypothesis that the total and/or phosphorylated protein content of key skeletal muscle markers of mitochondrial/oxidative metabolism and insulin-mediated signalling would be altered over 7d of SR in young healthy males.
METHODS: Eleven, healthy, recreationally active males (Mean ± SEM, age: 22±1yrs, BMI: 23.4±0.7 kg.m2) underwent a 7d period of SR. Immediately prior to and following SR, fasted-state muscle biopsy samples were acquired and analysed for the assessment of total of phosphorylated protein content of key markers of mitochondrial/oxidative metabolism and insulin-mediated signalling.
RESULTS: Daily step count was significantly reduced during the SR intervention (13054±833 to 1192±99 steps.d-1, P<0.001). Following SR there was a significant decline in maximal citrate synthase activity (Fold change: 0.94±0.08, P<0.05) and a significant increase in the protein content of p-glycogen synthase (P-GSS641; Fold change: 1.47±0.14, P<0.05). No significant differences were observed in the total or phosphorylated protein content of other key markers of insulin-mediated signalling, oxidative metabolism, mitochondrial function or mitochondrial dynamics (all P>0.05).
CONCLUSIONS: These results suggest that short-term SR reduces the maximal activity of citrate synthase, a marker of mitochondrial content, without altering the total or phosphorylated protein content of key markers of skeletal muscle mitochondrial metabolism and insulin signalling in young healthy males.

Keywords: Step reduction; insulin sensitivity; mitochondria; physical inactivity; skeletal muscle

DOI: https://doi.org/10.1152/japplphysiol.00650.2021

FASEB J. 2021 Dec;35(12): e22010

Mitochondrial NDUFA4L2 is a novel regulator of skeletal muscle mass and force.

Zhengye Liu, Thomas Chaillou, Estela Santos Alves, Theresa Mader, Baptiste Jude, Duarte M S Ferreira, Heidi Hynynen, Arthur J Cheng, William O Jonsson, Gianluigi Pironti, Daniel C Andersson, Ellinor Kenne, Jorge L Ruas, Pasi Tavi, Johanna T Lanner.

The hypoxia-inducible nuclear-encoded mitochondrial protein NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 4-like 2 (NDUFA4L2) has been demonstrated to decrease oxidative phosphorylation and production of reactive oxygen species in neonatal cardiomyocytes, brain tissue and hypoxic domains of cancer cells. Prolonged local hypoxia can negatively affect skeletal muscle size and tissue oxidative capacity. Although skeletal muscle is a mitochondrial rich, oxygen sensitive tissue, the role of NDUFA4L2 in skeletal muscle has not previously been investigated. Here we ectopically expressed NDUFA4L2 in mouse skeletal muscles using adenovirus-mediated expression and in vivo electroporation. Moreover, femoral artery ligation (FAL) was used as a model of peripheral vascular disease to induce hind limb ischemia and muscle damage. Ectopic NDUFA4L2 expression resulted in reduced mitochondrial respiration and reactive oxygen species followed by lowered AMP, ADP, ATP, and NAD+ levels without affecting the overall protein content of the mitochondrial electron transport chain. Furthermore, ectopically expressed NDUFA4L2 caused a ~20% reduction in muscle mass that resulted in weaker muscles. The loss of muscle mass was associated with increased gene expression of atrogenes MurF1 and Mul1, and apoptotic genes caspase 3 and Bax. Finally, we showed that NDUFA4L2 was induced by FAL and that the Ndufa4l2 mRNA expression correlated with the reduced capacity of the muscle to generate force after the ischemic insult. These results show, for the first time, that mitochondrial NDUFA4L2 is a novel regulator of skeletal muscle mass and force. Specifically, induced NDUFA4L2 reduces mitochondrial activity leading to lower levels of important intramuscular metabolites, including adenine nucleotides and NAD+ , which are hallmarks of mitochondrial dysfunction and hence shows that dysfunctional mitochondrial activity may drive muscle wasting.

Keywords: NDUFA4L2; mitochondria; muscle mass; skeletal muscle

DOI: https://doi.org/10.1096/fj.202100066R

Cell Prolif. 2021 Nov 01. e13155

Adiponectin receptor agonist AdipoRon blocks skin inflamm-ageing by regulating mitochondrial dynamics.

Jiachen Sun, Xinzhu Liu, Chuan'an Shen, Wen Zhang, Yuezeng Niu.

INTRODUCTION: Skin is susceptible to senescence-associated secretory phenotype (SASP) and inflamm-ageing partly owing to the degeneration of mitochondria. AdipoRon (AR) has protective effects on mitochondria in metabolic diseases such as diabetes. We explored the role of AR on mitochondria damage induced by skin inflamm-ageing and its underlying mechanism.
METHODS: Western blot, immunofluorescence and TUNEL staining were used to detect inflammatory factors and apoptosis during skin ageing. Transmission electron microscopy, ATP determination kit, CellLight Mitochondria GFP (Mito-GFP), mitochondrial stress test, MitoSOX and JC-1 staining were used to detect mitochondrial changes. Western blot was applied to explore the underlying mechanism. Flow cytometry, scratch test, Sulforhodamine B assay and wound healing test were used to detect the effects of AR on cell apoptosis, migration and proliferation.
RESULTS: AR attenuated inflammatory factors and apoptosis that increased in aged skin, and improved mitochondrial morphology and function. This process at least partly depended on the suppression of dynamin-related protein 1 (Drp1)-mediated excessive mitochondrial division. More specifically, AR up-regulated the phosphorylation of Drp1 at Serine 637 by activating AMP-activated protein kinase (AMPK), thereby inhibiting the mitochondrial translocation of Drp1. Moreover, AR reduced mitochondrial fragmentation and the production of superoxide, preserved the membrane potential and permeability of mitochondria and accelerated wound healing in aged skin.
CONCLUSION: AR rescues the mitochondria in aged skin by suppressing its excessive division mediated by Drp1.

Keywords: AdipoRon; Dynamin-related protein 1 (Drp1); SASP; inflamm-ageing; mitochondria; skin

DOI: https://doi.org/10.1111/cpr.13155