bims-misrem 2020-07-12 papers

bims-misrem

Biomed News

on Mitochondria and sarcoplasmic reticulum in muscle mass

Issue of 2020–07–12
six papers selected by
Rafael Antonio Casuso Pérez, University of Granada

Regular endurance exercise of overloaded muscle of young and old male mice does not attenuate hypertrophy and improves fatigue resistance.
Combining cooling or heating applications with exercise training to enhance performance and muscle adaptations.
Adolph Lecture: Skeletal Muscle Atrophy: Multiple Pathways Leading to a Common Outcome.
Mitochondrial ubiquinol oxidation is necessary for tumour growth.
Mitochondrial Dysfunction Is an Early Consequence of Partial or Complete Dystrophin Loss in mdx Mice.
Exercise adaptations: molecular mechanisms and potential targets for therapeutic benefit.

Geroscience. 2020 Jul 08.

Regular endurance exercise of overloaded muscle of young and old male mice does not attenuate hypertrophy and improves fatigue resistance.

Paul William Hendrickse, Raulas Krusnauskas, Emma Hodson-Tole, Tomas Venckunas, Hans Degens.

  It has been observed that there is an inverse relationship between fiber size and oxidative capacity due to oxygen, ADP, and ATP diffusion limitations. We aimed to see if regular endurance exercise alongside a hypertrophic stimulus would lead to compromised adaptations to both, particularly in older animals. Here we investigated the effects of combining overload with regular endurance exercise in young (12 months) and old (26 months) male mice. The plantaris muscles of these mice were overloaded through denervation of synergists to induce hypertrophy and the mice ran on a treadmill for 30 min per day for 6 weeks. The hypertrophic response to overload was not blunted by endurance exercise, and the increase in fatigue resistance with endurance exercise was not reduced by overload. Old mice demonstrated less hypertrophy than young mice, which was associated with impaired angiogenesis and a reduction in specific tension. The data of this study suggest that combining endurance exercise and overload induces the benefits of both types of exercise without compromising adaptations to either. Additionally, the attenuated hypertrophic response to overload in old animals may be due to a diminished capacity for capillary growth.

Keywords:  Ageing; Capillarization; Hypertrophy; Oxidative capacity

DOI:  https://doi.org/10.1007/s11357-020-00224-x
J Appl Physiol (1985). 2020 Jul 09.

Combining cooling or heating applications with exercise training to enhance performance and muscle adaptations.

Robert D Hyldahl, Jonathan M Peake.

  Athletes use cold water immersion, cryotherapy chambers or icing in the belief that these strategies improve postexercise recovery and promote greater adaptations to training. A number of studies have systematically investigated how regular cold water immersion influences long-term performance and muscle adaptations. The effects of regular cold water immersion after endurance or high-intensity interval training on aerobic capacity, lactate threshold, power output and time trial performance are equivocal. Evidence for changes in angiogenesis and mitochondrial biogenesis in muscle in response to regular cold water immersion is also mixed. More consistent evidence is available that regular cold water immersion after strength training attenuates gains in muscle mass and strength. These effects are attributable to reduced activation of satellite cells, ribosomal biogenesis, anabolic signaling and muscle protein synthesis. Athletes use passive heating to warm up before competition or improve postexercise recovery. Emerging evidence indicates that regular exposure to ambient heat, wearing garments perfused with hot water or microwave diathermy can mimic the effects of endurance training by stimulating angiogenesis and mitochondrial biogenesis in muscle. Some passive heating applications may also mitigate muscle atrophy through their effects on mitochondrial biogenesis and muscle fiber hypertrophy. More research is needed to consolidate these findings, however. Future research in this field should focus on (1) the optimal modality, temperature, duration and frequency of cooling and heating to enhance long-term performance and muscle adaptations and (2) whether molecular and morphological changes in muscle in response to cooling and heating applications translate to improvements in exercise performance.

Keywords:  adaptations; cold water immersion; cryotherapy; passive heating; performance

DOI:  https://doi.org/10.1152/japplphysiol.00322.2020
J Appl Physiol (1985). 2020 Jul 09.

Adolph Lecture: Skeletal Muscle Atrophy: Multiple Pathways Leading to a Common Outcome.

Sue C Bodine.

  Skeletal muscle atrophy continues to be a serious consequence of many diseases and conditions for which there is no treatment. Our understanding of the mechanisms regulating skeletal muscle mass has improved considerably over the past two decades. For many years it was known that skeletal muscle atrophy resulted from an imbalance between protein synthesis and protein breakdown, with the net balance shifting towards protein breakdown. However, the molecular and cellular mechanisms underlying the increased breakdown of myofibrils was unknown. Over the past two decades, numerous reports have identified novel genes and signaling pathways that are upregulated and activated in response to stimuli such as disuse, inflammation, metabolic stress, starvation and others that induce muscle atrophy. This review summarizes the discovery efforts performed in the identification of several pathways involved in the regulation of skeletal muscle mass: the mammalian target of rapamycin (mTORC1) and the ubiquitin proteasome pathway and the E3 ligases, MuRF1 and MAFbx. While muscle atrophy is a common outcome of many diseases, it is doubtful that a single gene or pathway initiates or mediates the breakdown of myofibrils. Interestingly, however, is the observation that upregulation of the E3 ligases, MuRF1 and MAFbx, is a common feature of many divergent atrophy conditions. The challenge for the field of muscle biology is to understand how all of the various molecules, transcription factors, and signaling pathways interact to produce muscle atrophy and to identify the critical factors for intervention.

Keywords:  MAFbx; MuRF1; mTORC1; protein synthesis; ubiquitin proteasome pathway

DOI:  https://doi.org/10.1152/japplphysiol.00381.2020
Nature. 2020 Jul 08.

Mitochondrial ubiquinol oxidation is necessary for tumour growth.

Inmaculada Martínez-Reyes, Luzivette Robles Cardona, Hyewon Kong, Karthik Vasan, Gregory S McElroy, Marie Werner, Hermon Kihshen, Colleen R Reczek, Samuel E Weinberg, Peng Gao, Elizabeth M Steinert, Raul Piseaux, G R Scott Budinger, Navdeep S Chandel.

The mitochondrial electron transport chain (ETC) is necessary for tumour growth1-6 and its inhibition has demonstrated anti-tumour efficacy in combination with targeted therapies7-9. Furthermore, human brain and lung tumours display robust glucose oxidation by mitochondria10,11. However, it is unclear why a functional ETC is necessary for tumour growth in vivo. ETC function is coupled to the generation of ATP-that is, oxidative phosphorylation and the production of metabolites by the tricarboxylic acid (TCA) cycle. Mitochondrial complexes I and II donate electrons to ubiquinone, resulting in the generation of ubiquinol and the regeneration of the NAD+ and FAD cofactors, and complex III oxidizes ubiquinol back to ubiquinone, which also serves as an electron acceptor for dihydroorotate dehydrogenase (DHODH)-an enzyme necessary for de novo pyrimidine synthesis. Here we show impaired tumour growth in cancer cells that lack mitochondrial complex III. This phenotype was rescued by ectopic expression of Ciona intestinalis alternative oxidase (AOX)12, which also oxidizes ubiquinol to ubiquinone. Loss of mitochondrial complex I, II or DHODH diminished the tumour growth of AOX-expressing cancer cells deficient in mitochondrial complex III, which highlights the necessity of ubiquinone as an electron acceptor for tumour growth. Cancer cells that lack mitochondrial complex III but can regenerate NAD+ by expression of the NADH oxidase from Lactobacillus brevis (LbNOX)13 targeted to the mitochondria or cytosol were still unable to grow tumours. This suggests that regeneration of NAD+ is not sufficient to drive tumour growth in vivo. Collectively, our findings indicate that tumour growth requires the ETC to oxidize ubiquinol, which is essential to drive the oxidative TCA cycle and DHODH activity.

DOI: https://doi.org/10.1038/s41586-020-2475-6
Front Physiol. 2020 ;11 690

Mitochondrial Dysfunction Is an Early Consequence of Partial or Complete Dystrophin Loss in mdx Mice.

Timothy M Moore, Amanda J Lin, Alexander R Strumwasser, Kevin Cory, Kate Whitney, Theodore Ho, Timothy Ho, Joseph L Lee, Daniel H Rucker, Christina Q Nguyen, Aidan Yackly, Sushil K Mahata, Jonathan Wanagat, Linsey Stiles, Lorraine P Turcotte, Rachelle H Crosbie, Zhenqi Zhou.

  Duchenne muscular dystrophy (DMD) is characterized by rapid wasting of skeletal muscle. Mitochondrial dysfunction is a well-known pathological feature of DMD. However, whether mitochondrial dysfunction occurs before muscle fiber damage in DMD pathology is not well known. Furthermore, the impact upon heterozygous female mdx carriers (mdx/+), who display dystrophin mosaicism, has received little attention. We hypothesized that dystrophin deletion leads to mitochondrial dysfunction, and that this may occur before myofiber necrosis. As a secondary complication to mitochondrial dysfunction, we also hypothesized metabolic abnormalities prior to the onset of muscle damage. In this study, we detected aberrant mitochondrial morphology, reduced cristae number, and large mitochondrial vacuoles from both male and female mdx mice prior to the onset of muscle damage. Furthermore, we systematically characterized mitochondria during disease progression starting before the onset of muscle damage, noting additional changes in mitochondrial DNA copy number and regulators of mitochondrial size. We further detected mild metabolic and mitochondrial impairments in female mdx carrier mice that were exacerbated with high-fat diet feeding. Lastly, inhibition of the strong autophagic program observed in adolescent mdx male mice via administration of the autophagy inhibitor leupeptin did not improve skeletal muscle pathology. These results are in line with previous data and suggest that before the onset of myofiber necrosis, mitochondrial and metabolic abnormalities are present within the mdx mouse.

Keywords:  Duchenne muscular dystrophy; autophagy; dystrophin; metabolism; mitochondria; muscular dystrophy; skeletal muscle

DOI:  https://doi.org/10.3389/fphys.2020.00690
Nat Rev Endocrinol. 2020 Jul 06.

Exercise adaptations: molecular mechanisms and potential targets for therapeutic benefit.

Sean L McGee, Mark Hargreaves.

Exercise is fundamental for good health, whereas physical inactivity underpins many chronic diseases of modern society. It is well appreciated that regular exercise improves metabolism and the metabolic phenotype in a number of tissues. The phenotypic alterations observed in skeletal muscle are partly mediated by transcriptional responses that occur following each individual bout of exercise. This adaptive response increases oxidative capacity and influences the function of myokines and extracellular vesicles that signal to other tissues. Our understanding of the epigenetic and transcriptional mechanisms that mediate the skeletal muscle gene expression response to exercise as well as of their upstream signalling pathways has advanced substantially in the past 10 years. With this knowledge also comes the opportunity to design new therapeutic strategies based on the biology of exercise for a variety of chronic conditions where regular exercise might be a challenge. This Review provides an overview of the beneficial adaptive responses to exercise and details the molecular mechanisms involved. The possibility of designing therapeutic interventions based on these molecular mechanisms is addressed, using relevant examples that have exploited this approach.

DOI: https://doi.org/10.1038/s41574-020-0377-1