bims-misrem 2021-08-01 papers

Front Physiol. 2021 ;12 707634

Mitofusin-2 Enhances Mitochondrial Contact With the Endoplasmic Reticulum and Promotes Diabetic Cardiomyopathy.

Diabetic cardiomyopathy has been associated with mitochondrial damage. Mitochondria-endoplasmic reticulum (ER) contact is an important determinant of mitochondrial function and ER homeostasis. We therefore investigated whether hyperglycemia can damage the mitochondria by increasing their contact with the ER in cardiomyocytes. We found that hyperglycemia induced mitochondria-ER contact in cardiomyocytes, as evidenced by the increased MMM1, MDM34, and BAP31 expressions. Interestingly, the silencing of Mfn2 reduced the cooperation between the mitochondria and the ER in cardiomyocytes. Mfn2 silencing improved cardiomyocyte viability and function under hyperglycemic conditions. Additionally, the silencing of Mfn2 markedly attenuated the release of calcium from the ER to the mitochondria, thereby preserving mitochondrial metabolism in cardiomyocytes under hyperglycemic conditions. Mfn2 silencing reduced mitochondrial reactive oxygen species production, which reduced mitochondria-dependent apoptosis in hyperglycemia-treated cardiomyocytes. Finally, Mfn2 silencing attenuated ER stress in cardiomyocytes subjected to high-glucose stress. These results demonstrate that Mfn2 promotes mitochondria-ER contact in hyperglycemia-treated cardiomyocytes. The silencing of Mfn2 sustained mitochondrial function, suppressed mitochondrial calcium overload, prevented mitochondrial apoptosis, and reduced ER stress, thereby enhancing cardiomyocyte survival under hyperglycemic conditions.

Keywords: ER; Mfn2; apoptosis; mitochondria; mitochondria-ER contact

DOI: https://doi.org/10.3389/fphys.2021.707634

J Physiol. 2021 Jul 28.

Early resistance training-mediated stimulation of daily muscle protein synthetic responses to higher habitual protein intake in middle-aged adults.

Amadeo F Salvador, Colleen F McKenna, Kevin J M Paulussen, Alexander R Keeble, Andrew T Askow, Hsin-Yu Fang, Zhong Li, Alexander V Ulanov, Scott A Paluska, Daniel R Moore, Nicholas A Burd.

KEY POINTS: The ingestion of protein potentiates the stimulation of myofibrillar protein synthesis rates after an acute bout of resistance exercise. Protein supplementation (eating above the protein Recommended Dietary Allowance) during resistance training has been shown to maximize lean mass and strength gains in healthy young and older adults. Here, we assessed contractile, oxidative, and structural protein synthesis in skeletal muscle in response to a moderate or higher protein diet during the early adaptive phase of resistance training in middle-aged adults. We report that the stimulation of myofibrillar, mitochondrial, or collagen protein synthesis rates during 0-3 weeks of resistance training is not further enhanced by a higher protein diet. These results show that moderate protein diets are sufficient to support the skeletal muscle adaptive response during the early phase of a resistance training program.
ABSTRACT: Protein ingestion augments muscle protein synthesis (MPS) rates acutely after resistance exercise and can offset age-related loss in muscle mass. Skeletal muscle contains a variety of protein pools, such as myofibrillar (contractile), mitochondrial (substrate oxidation), and collagen (structural support) proteins, and the sensitivity to nutrition and exercise seems to be dependent on the major protein fraction studied. However, it is unknown how free-living conditions of dietary protein density with habitual resistance exercise mediates muscle protein subfraction synthesis. Therefore, we investigated the effect of moderate (MOD: 1.06 ± 0.22 g·kg-1 ·d-1 ) or high (HIGH: 1.55 ± 0.25 g·kg-1 ·d-1 ) protein intake on daily MPS rates within the myofibrillar (MyoPS), mitochondrial (MitoPS), and collagen (CPS) protein fractions in middle-aged men and women (n = 20, 47 ± 1 y, BMI 28 ± 1 kg·m-2 ) during the early phase (0-3 wks) of a dietary counseling-controlled resistance training program. Participants were loaded with deuterated water, followed by daily maintenance doses throughout the intervention. Muscle biopsies were collected at baseline and after weeks 1, 2, and 3. MyoPS in the HIGH condition remained constant (P = 1.000), but MOD decreased over time (P = 0.023). MitoPS decreased after 0-3 wks when compared to 0-1 wks (P = 0.010) with no effects of protein intake (P = 0.827). A similar decline with no difference between groups (P = 0.323) was also observed for CPS (P = 0.007). Our results demonstrated that additional protein intake above moderate amounts does not potentiate the stimulation of longer-term MPS responses during the early stage of resistance training adaptations in middle-aged adults. This article is protected by copyright. All rights reserved.

Keywords: YAP; aging; deuterium oxide; mTORC1

DOI: https://doi.org/10.1113/JP281907

Physiol Rep. 2021 Aug;9(15): e14962

Individual physiological and mitochondrial responses during 12 weeks of intensified exercise.

Macsue Jacques, Shanie Landen, Javier Alvarez Romero, Xu Yan, Andrew Garnham, Danielle Hiam, Mélina Siegwald, Emma Mercier, Anne Hecksteden, Nir Eynon, Sarah Voisin.

AIM: Observed effects of exercise are highly variable between individuals, and subject-by-training interaction (i.e., individual response variability) is often not estimated. Here, we measured mitochondrial (citrate synthetase, cytochrome-c oxidase, succinate dehydrogenase, and mitochondrial copy-number), performance markers (Wpeak , lactate threshold [LT], and VO2peak ), and fiber type proportions/expression (type I, type IIa, and type IIx) in multiple time points during 12-week of high-intensity interval training (HIIT) to investigate effects of exercise at the individual level.
METHODS: Sixteen young (age: 33.1 ± 9.0 years), healthy men (VO2peak 35-60 ml/min/kg and BMI: 26.4 ± 4.2) from the Gene SMART study completed 12-week of progressive HIIT. Performance markers and muscle biopsies were collected every 4 weeks. We used mixed-models and bivariate growth models to quantify individual response and to estimate correlations between variables.
RESULTS: All performance markers exhibited significant (Wpeak 0.56 ± 0.33 p = 0.003, LT 0.37 ± 0.35 p = 0.007, VO2peak 3.81 ± 6.13 p = 0.02) increases overtime, with subject-by-training interaction being present (95% CI: Wpeak 0.09-0.24, LT 0.06-0.18, VO2peak 0.27-2.32). All other measurements did not exhibit significant changes. Fiber type IIa proportions at baseline was significantly associated with all physiological variables (p < 0.05), and citrate synthetase and cytochrome-c oxidase levels at baseline and overtime (i.e., intercept and slope) presented significant covariance (p < 0.05). Finally, low correlations between performance and mitochondrial markers were observed.
CONCLUSION: We identified a significant subject-by-training interaction for the performance markers. While for all other measures within-subject variability was too large and interindividual differences in training efficacy could not be verified. Changes in measurements in response to exercise were not correlated, and such disconnection should be further investigated by future studies.

Keywords: VO2peak; exercise; mitochondria; training variability

DOI: https://doi.org/10.14814/phy2.14962

J Cell Sci. 2021 07 01. pii: jcs252197. [Epub ahead of print]134(13):

Super-resolution microscopy reveals the arrangement of inner membrane protein complexes in mammalian mitochondria.

Catherine S Palmer, Jieqiong Lou, Betty Kouskousis, Elvis Pandzic, Alexander J Anderson, Yilin Kang, Elizabeth Hinde, Diana Stojanovski.

The mitochondrial inner membrane is a protein-rich environment containing large multimeric complexes, including complexes of the mitochondrial electron transport chain, mitochondrial translocases and quality control machineries. Although the inner membrane is highly proteinaceous, with 40-60% of all mitochondrial proteins localised to this compartment, little is known about the spatial distribution and organisation of complexes in this environment. We set out to survey the arrangement of inner membrane complexes using stochastic optical reconstruction microscopy (STORM). We reveal that subunits of the TIM23 complex, TIM23 and TIM44 (also known as TIMM23 and TIMM44, respectively), and the complex IV subunit COXIV, form organised clusters and show properties distinct from the outer membrane protein TOM20 (also known as TOMM20). Density based cluster analysis indicated a bimodal distribution of TIM44 that is distinct from TIM23, suggesting distinct TIM23 subcomplexes. COXIV is arranged in larger clusters that are disrupted upon disruption of complex IV assembly. Thus, STORM super-resolution microscopy is a powerful tool for examining the nanoscale distribution of mitochondrial inner membrane complexes, providing a 'visual' approach for obtaining pivotal information on how mitochondrial complexes exist in a cellular context.

Keywords: COXIV; Mitochondria; Mitochondrial complexes; Nanoscopy; Protein import; STORM; TIM23

DOI: https://doi.org/10.1242/jcs.252197