bims-misrem 2021-09-26 papers

Free Radic Biol Med. 2021 Sep 21. pii: S0891-5849(21)00726-7. [Epub ahead of print]

Promoting a pro-oxidant state in skeletal muscle: Potential dietary, environmental, and exercise interventions for enhancing endurance-training adaptations.

Adam C Jordan, Christopher G R Perry, Arthur J Cheng.

Accumulating evidence now shows that supplemental antioxidants including vitamin C, vitamin E and N-Acetylcysteine consumption can suppress adaptations to endurance-type exercise by attenuating reactive oxygen and nitrogen species (RONS) formation within skeletal muscle. This emerging evidence points to the importance of pro-oxidation as an important stimulus for endurance-training adaptations, including mitochondrial biogenesis, endogenous antioxidant production, insulin signalling, angiogenesis and growth factor signaling. Although sustained oxidative distress is associated with many chronic diseases, athletes have, on average, elevated levels of certain endogenous antioxidants to maintain redox homeostasis. As a result, trained athletes may have a better capacity to buffer oxidants during and after exercise, resulting in a reduced oxidative eustress stimulus for adaptations. Thus, higher levels of RONS input and exercise-induced oxidative stress may benefit athletes in the pursuit of continuous endurance training redox adaptations. This review addresses why athletes should be looking to enhance exercise-induced oxidative stress and how it can be accomplished. Methods covered include high-intensity interval training, hyperthermia and heat stress, dietary antioxidant restriction and modified antioxidant timing, dietary antioxidants and polyphenols as adjuncts to exercise, and vitamin C as a pro-oxidant.

Keywords: Antioxidants; Endurance training; Exercise adaptations; High-intensity interval training; Hormesis; Oxidative distress; Oxidative eustress; Oxidative stress; Prooxidants; Skeletal muscle; Sprint interval training

DOI: https://doi.org/10.1016/j.freeradbiomed.2021.09.014

Am J Physiol Regul Integr Comp Physiol. 2021 Sep 22.

Acute high-intensity exercise and skeletal muscle mitochondrial respiratory function: The role of metabolic perturbation.

Matthew T Lewis, Grégory M Blain, Corey R Hart, Gwenael Layec, Matthew J Rossman, Song-Young Park, Joel D Trinity, Jayson R Gifford, Simranjit K Sidhu, Joshua C Weavil, Thomas J Hureau, Jacob E Jessop, Amber D Bledsoe, Markus Amann, Russell S Richardson.

Recently it was documented that, fatiguing, high-intensity exercise resulted in a significant attenuation in maximal skeletal muscle mitochondrial respiratory capacity, potentially due to the intramuscular metabolic perturbation elicited by such intense exercise. Utilizing intrathecal fentanyl to attenuate afferent feedback from group III/IV muscle afferents, permitting increased muscle activation and greater intramuscular metabolic disturbance, this study aimed to better elucidate the role of metabolic perturbation on mitochondrial respiratory function. Eight young, healthy males performed high-intensity cycle exercise in control (CTRL) and fentanyl-treated (FENT) conditions. Liquid chromatography-mass spectrometry and high resolution respirometry were employed to assess metabolites and mitochondrial respiratory function, respectively, pre- and post-exercise in muscle biopsies from the vastus lateralis. Compared to CTRL, FENT yielded a significantly greater exercise-induced metabolic perturbation (PCr: -67 vs. -82%, Pi: 353 vs. 534%, pH:-0.22 vs. -0.31, lactate: 820 vs. 1160%). Somewhat surprisingly, despite this greater metabolic perturbation in FENT compared to CTRL, with the only exception of respiratory control ratio (RCR) (-3 and -36%) for which the impact of FENT was significantly greater, the degree of attenuated mitochondrial respiratory capacity post-exercise was not different between CTRL and FENT, respectively, as assessed by maximal respiratory flux through complex I (-15 and -33%), complex II (-36% and -23%), complex I+II (-31 and -20%), and state 3CI+CII control ratio (-24 and -39%). Although a basement effect cannot be ruled out, this failure of an augmented metabolic perturbation to extensively further attenuate mitochondrial function questions the direct role of high-intensity exercise-induced metabolite accumulation in this post exercise response.

Keywords: mitochondrial function; muscle afferents; muscle metabolites; oxidative phosphorylation

DOI: https://doi.org/10.1152/ajpregu.00158.2021

Mitochondrion. 2021 Sep 15. pii: S1567-7249(21)00121-5. [Epub ahead of print]

Mitofusin 2: A Link Between Mitochondrial Function and Substrate Metabolism?

Janna M Emery, Rudy M Ortiz.

Mitochondria are dynamic, interactive organelles that connect cellular signaling and whole-cell homeostasis. This "mitochatting" allows the cell to receive information about the mitochondria's condition before accommodating energy demands. Mitofusin 2 (Mfn2), an outer mitochondrial membrane fusion protein specializes in mediating mitochondrial homeostasis. Early studies defined the biological significance of Mfn2, latter studies highlighted its role in substrate metabolism. However, determining Mfn2 potential to contribute to energy homeostasis needs study. This review summarizes current literature on mitochondrial metabolic processes, dynamics, and evidence of interactions among Mfn2 and regulatory processes that may link Mfn2's role in maintaining mitochondrial function and substrate metabolism.

Keywords: fatty acid oxidation; fission; fusion; glycolysis; mitochondrial dynamics; mitophagy

DOI: https://doi.org/10.1016/j.mito.2021.09.003

Aging Cell. 2021 Sep 23. e13467

Late-in-life treadmill training rejuvenates autophagy, protein aggregate clearance, and function in mouse hearts.

Jae Min Cho, Seul-Ki Park, Rajeshwary Ghosh, Kellsey Ly, Caroline Ramous, Lauren Thompson, Michele Hansen, Maria Sara de Lima Coutinho Mattera, Karla Maria Pires, Maroua Ferhat, Sohom Mookherjee, Kevin J Whitehead, Kandis Carter, Márcio Buffolo, Sihem Boudina, J David Symons.

Protein quality control mechanisms decline during the process of cardiac aging. This enables the accumulation of protein aggregates and damaged organelles that contribute to age-associated cardiac dysfunction. Macroautophagy is the process by which post-mitotic cells such as cardiomyocytes clear defective proteins and organelles. We hypothesized that late-in-life exercise training improves autophagy, protein aggregate clearance, and function that is otherwise dysregulated in hearts from old vs. adult mice. As expected, 24-month-old male C57BL/6J mice (old) exhibited repressed autophagosome formation and protein aggregate accumulation in the heart, systolic and diastolic dysfunction, and reduced exercise capacity vs. 8-month-old (adult) mice (all p < 0.05). To investigate the influence of late-in-life exercise training, additional cohorts of 21-month-old mice did (old-ETR) or did not (old-SED) complete a 3-month progressive resistance treadmill running program. Body composition, exercise capacity, and soleus muscle citrate synthase activity improved in old-ETR vs. old-SED mice at 24 months (all p < 0.05). Importantly, protein expression of autophagy markers indicate trafficking of the autophagosome to the lysosome increased, protein aggregate clearance improved, and overall function was enhanced (all p < 0.05) in hearts from old-ETR vs. old-SED mice. These data provide the first evidence that a physiological intervention initiated late-in-life improves autophagic flux, protein aggregate clearance, and contractile performance in mouse hearts.

Keywords: aging; cardiac function; exercise; protein aggregates

DOI: https://doi.org/10.1111/acel.13467

Cell Syst. 2021 Sep 16. pii: S2405-4712(21)00338-0. [Epub ahead of print]

NAD+ flux is maintained in aged mice despite lower tissue concentrations.

NAD+ is an essential coenzyme for all living cells. NAD+ concentrations decline with age, but whether this reflects impaired production or accelerated consumption remains unclear. We employed isotope tracing and mass spectrometry to probe age-related changes in NAD+ metabolism across tissues. In aged mice, we observed modest tissue NAD+ depletion (median decrease ∼30%). Circulating NAD+ precursors were not significantly changed, and isotope tracing showed the unimpaired synthesis of nicotinamide from tryptophan. In most tissues of aged mice, turnover of the smaller tissue NAD+ pool was modestly faster such that absolute NAD+ biosynthetic flux was maintained, consistent with more active NAD+-consuming enzymes. Calorie restriction partially mitigated age-associated NAD+ decline by decreasing consumption. Acute inflammatory stress induced by LPS decreased NAD+ by impairing synthesis in both young and aged mice. Thus, the decline in NAD+ with normal aging is relatively subtle and occurs despite maintained NAD+ production, likely due to increased consumption.

Keywords: CD38; NAD; NADH; PARP; PARP1; SIRT1; aging; flux; mononucleotide; niacin; nicotinamide; redox; riboside; sirtuins

DOI: https://doi.org/10.1016/j.cels.2021.09.001