bims-moremu 2023-12-31 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2023–12–31
nineteen papers selected by
Anna Vainshtein, Craft Science Inc.

The slow-release adiponectin analogue ALY688-SR modifies early-stage disease development in the D2.mdx mouse model of Duchenne muscular dystrophy.
Resistance-only and concurrent exercise induce similar myofibrillar protein synthesis rates and associated molecular responses in moderately active men before and after training.
A muscle exercise research revolution powered by -omics at single cell and nucleus resolution.
Overexpression of manganese superoxide dismutase mitigates ACL injury-induced muscle atrophy, weakness and oxidative damage.
Scheduled for surgery? Prescription: exercise!
Distinct lactate metabolism between hepatocytes and myotubes revealed by live cell imaging with genetically encoded indicators.
Molecular profiling of high-level athlete skeletal muscle after acute endurance or resistance exercise - a systems biology approach.
Impact of fasting on the AMPK and PGC-1α axis in rodent and human skeletal muscle: A systematic review.
The muscle stem cell niche at a glance.
Combination of chemotherapy and antioxidants: promising therapeutic strategies for muscle atrophy during cancer treatment.
The epigenetic regulatory effect of histone acetylation and deacetylation on skeletal muscle metabolism-a review.
Age-related changes of skeletal muscle metabolic response to contraction are also sex-dependent.
Role of PPARα in inflammatory response of C2C12 myotubes.
Increased Expression of MiRNA-1 Contributes to Hypobaric Hypoxia-Induced Skeletal Muscle Loss.
Mitochondrial electron transport chain, ceramide, and coenzyme Q are linked in a pathway that drives insulin resistance in skeletal muscle.
Association of skeletal muscle oxidative capacity with muscle function, sarcopenia-related exercise performance, and intramuscular adipose tissue in older adults.
Potentiation of force by extracellular potassium is not dependent on muscle length in mouse EDL muscle.
Skeletal muscle energetics explain the sex disparity in mobility impairment in the Study of Muscle, Mobility and Aging (SOMMA).
Effects of resistance training on alleviating hypoxia-induced muscle atrophy: Focus on acetylation of FoxO1.

Am J Physiol Cell Physiol. 2023 Dec 25.

The slow-release adiponectin analogue ALY688-SR modifies early-stage disease development in the D2.mdx mouse model of Duchenne muscular dystrophy.

Catherine A Bellissimo, Shivam Gandhi, Laura N Castellani, Mayoorey Murugathasan, Luca J Delfinis, Arshdeep Thuhan, Madison C Garibotti, Yeji Seo, Irena A Rebalka, Henry H Hsu, Gary Sweeney, Thomas J Hawke, Ali A Abdul-Sater, Christopher G R Perry.

  Fibrosis is associated with respiratory and limb muscle atrophy in Duchenne muscular dystrophy (DMD). Current standard of care partially delays the progression of this myopathy but there remains an unmet need to develop additional therapies. Adiponectin receptor agonism has emerged as a possible therapeutic target to lower inflammation and improve metabolism in mdx mouse models of DMD but the degree to which fibrosis and atrophy are prevented remain unknown. Here, we demonstrate that the recently developed slow-release peptidomimetic adiponectin analogue, ALY688-SR, remodels the diaphragm of D2.mdx mice treated from days 7-28 of age during early stages of disease. ALY688-SR also lowered IL-6mRNA but increased IL-6 and TGF-β1 protein contents in diaphragm, suggesting dynamic inflammatory remodeling. ALY688-SR alleviated mitochondrial redox stress by decreasing complex I-stimulated H2O2 emission. Treatment also lowered in vitro diaphragm force production in diaphragm suggesting a complex relationship between adiponectin receptor activity, muscle remodeling and force generating properties during the very early stages of disease progression in D2.mdx mice. In tibialis anterior, the modest fibrosis at this young age was not altered by treatment, and atrophy was not apparent at this young age. These results demonstrate that short-term treatment of ALY688-SR in young D2. mdx mice partially prevents fibrosis and fibre type-specific atrophy and lowered force production in the more disease-apparent diaphragm in relation to lower mitochondrial redox stress and heterogeneous responses in certain inflammatory markers. These diverse muscle responses to adiponectin receptor agonism in early stages of DMD serve as a foundation for further mechanistic investigations.

Keywords:  adiponectin receptor agonism; atrophy; duchenne muscular dystrophy; fibrosis; muscle

DOI:  https://doi.org/10.1152/ajpcell.00638.2023
FASEB J. 2024 Jan;38(1): e23392

Resistance-only and concurrent exercise induce similar myofibrillar protein synthesis rates and associated molecular responses in moderately active men before and after training.

Matthew J Lee, Nikeisha J Caruana, Nicholas J Saner, Jujiao Kuang, Tanner Stokes, Jonathan C McLeod, Sara Y Oikawa, David J Bishop, Jonathan D Bartlett, Stuart M Phillips.

  Aerobic and resistance exercise (RE) induce distinct molecular responses. One hypothesis is that these responses are antagonistic and unfavorable for the anabolic response to RE when concurrent exercise is performed. This thesis may also depend on the participants' training status and concurrent exercise order. We measured free-living myofibrillar protein synthesis (MyoPS) rates and associated molecular responses to resistance-only and concurrent exercise (with different exercise orders), before and after training. Moderately active men completed one of three exercise interventions (matched for age, baseline strength, body composition, and aerobic capacity): resistance-only exercise (RE, n = 8), RE plus high-intensity interval exercise (RE+HIIE, n = 8), or HIIE+RE (n = 9). Participants trained 3 days/week for 10 weeks; concurrent sessions were separated by 3 h. On the first day of Weeks 1 and 10, muscle was sampled immediately before and after, and 3 h after each exercise mode and analyzed for molecular markers of MyoPS and muscle glycogen. Additional muscle, sampled pre- and post-training, was used to determine MyoPS using orally administered deuterium oxide (D2 O). In both weeks, MyoPS rates were comparable between groups. Post-exercise changes in proteins reflective of protein synthesis were also similar between groups, though MuRF1 and MAFbx mRNA exhibited some exercise order-dependent responses. In Week 10, exercise-induced changes in MyoPS and some genes (PGC-1ɑ and MuRF1) were dampened from Week 1. Concurrent exercise (in either order) did not compromise the anabolic response to resistance-only exercise, before or after training. MyoPS rates and some molecular responses to exercise are diminished after training.

Keywords:  MPS; exercise order; glycogen; mRNA; signaling; training status

DOI:  https://doi.org/10.1096/fj.202302024R
BMC Biol. 2023 Dec 29. 21(1): 298

A muscle exercise research revolution powered by -omics at single cell and nucleus resolution.

Kevin A Murach, Charlotte A Peterson.

DOI: https://doi.org/10.1186/s12915-023-01781-1
Free Radic Biol Med. 2023 Dec 26. pii: S0891-5849(23)01193-0. [Epub ahead of print]

Overexpression of manganese superoxide dismutase mitigates ACL injury-induced muscle atrophy, weakness and oxidative damage.

Christine M Latham, Peyton J Balawender, Nicholas T Thomas, Alexander R Keeble, Camille R Brightwell, Ahmed Ismaeel, Yuan Wen, Jean L Fry, Patrick G Sullivan, Darren L Johnson, Brian Noehren, Allison M Owen, Christopher S Fry.

  Oxidative stress has been implicated in the etiology of skeletal muscle weakness following joint injury. We investigated longitudinal patient muscle samples following knee injury (anterior cruciate ligament tear). Following injury, transcriptomic analysis revealed downregulation of mitochondrial metabolism-related gene networks, which were supported by reduced mitochondrial respiratory flux rates. Additionally, enrichment of reactive oxygen species (ROS)-related pathways were upregulated in muscle following knee injury, and further investigation unveiled marked oxidative damage in a progressive manner following injury and surgical reconstruction. We then investigated whether antioxidant protection is effective in preventing muscle atrophy and weakness after knee injury in mice that overexpress Mn-Superoxide dismutase (MnSOD+/-). MnSOD ± mice showed attenuated oxidative damage, atrophy, and muscle weakness compared to wild type littermate controls following ACL transection surgery. Taken together, our results indicate that ROS-related damage is a causative mechanism of muscle dysfunction after knee injury, and that mitochondrial antioxidant protection may hold promise as a therapeutic target to prevent weakness and development of disability.

Keywords:  Anterior cruciate ligament; Knee injury; Mitochondria; Quadriceps; Reactive oxygen species; Skeletal muscle

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.12.037
J Physiol. 2023 Dec 25.

Scheduled for surgery? Prescription: exercise!

Casper Soendenbroe, Grith Højfeldt.



Keywords:  ageing; disuse; prehabilitation; prehabilitative exercise; skeletal muscle

DOI:  https://doi.org/10.1113/JP285971
Biochem Biophys Res Commun. 2023 Dec 20. pii: S0006-291X(23)01510-3. [Epub ahead of print]694 149416

Distinct lactate metabolism between hepatocytes and myotubes revealed by live cell imaging with genetically encoded indicators.

Mina Horikoshi, Kazuki Harada, Saki Tsuno, Tetsuya Kitaguchi, Masami Yokota Hirai, Mitsuharu Matsumoto, Shin Terada, Takashi Tsuboi.

  The process of glycolysis breaks down glycogen stored in muscles, producing lactate through pyruvate to generate energy. Excess lactate is then released into the bloodstream. When lactate reaches the liver, it is converted to glucose, which muscles utilize as a substrate to generate ATP. Although the biochemical study of lactate metabolism in hepatocytes and skeletal muscle cells has been extensive, the spatial and temporal dynamics of this metabolism in live cells are still unknown. We observed the dynamics of metabolism-related molecules in primary cultured hepatocytes and a skeletal muscle cell line upon lactate overload. Our observations revealed an increase in cytoplasmic pyruvate concentration in hepatocytes, which led to glucose release. Skeletal muscle cells exhibited elevated levels of lactate and pyruvate levels in both the cytoplasm and mitochondrial matrix. However, mitochondrial ATP levels remained unaffected, indicating that the increased lactate can be converted to pyruvate but is unlikely to be utilized for ATP production. The findings suggest that excess lactate in skeletal muscle cells is taken up into mitochondria with little contribution to ATP production. Meanwhile, lactate released into the bloodstream can be converted to glucose in hepatocytes for subsequent utilization in skeletal muscle cells.

Keywords:  Cori cycle; Hepatocytes; L6 cells; Lactate metabolism; Live cell imaging

DOI:  https://doi.org/10.1016/j.bbrc.2023.149416
Mol Metab. 2023 Dec 21. pii: S2212-8778(23)00191-6. [Epub ahead of print] 101857

Molecular profiling of high-level athlete skeletal muscle after acute endurance or resistance exercise - a systems biology approach.

Stefan M Reitzner, Eric B Emanuelsson, Muhammad Arif, Bogumil Kaczkowski, Andrew Tj Kwon, Adil Mardinoglu, Erik Arner, Mark A Chapman, Carl Johan Sundberg.

   OBJECTIVE: Long-term high-level exercise training leads to improvements in physical performance and multi-tissue adaptation following changes in molecular pathways. While skeletal muscle baseline differences between exercise-trained and untrained individuals have been previously investigated, it remains unclear how training history influences human multi-omics responses to acute exercise.
METHODS: We recruited and extensively characterized 24 individuals categorized as endurance athletes with >15 years of training history, strength athletes or control subjects. Timeseries skeletal muscle biopsies were taken from M. vastus lateralis at three time-points after endurance or resistance exercise was performed and multi-omics molecular analysis performed.
RESULTS: Our analyses revealed distinct activation differences of molecular processes such as fatty- and amino acid metabolism and transcription factors such as HIF1A and the MYF-family. We show that endurance athletes have an increased abundance of carnitine-derivates while strength athletes increase specific phospholipid metabolites compared to control subjects. Additionally, for the first time, we show the metabolite sorbitol to be substantially increased with acute exercise. On transcriptional level, we show that acute resistance exercise stimulates more gene expression than acute endurance exercise. This follows a specific pattern, with endurance athletes uniquely down-regulating pathways related to mitochondria, translation and ribosomes. Finally, both forms of exercise training specialize in diverging transcriptional directions, differentiating themselves from the transcriptome of the untrained control group.
CONCLUSIONS: We identify a "transcriptional specialization effect" by transcriptional narrowing and intensification, and molecular specialization effects on metabolomic level Additionally, we performed multi-omics network and cluster analysis, providing a novel resource of skeletal muscle transcriptomic and metabolomic profiling in highly trained and untrained individuals.

Keywords:  athletes; human; metabolomics; molecular exercise effects; multi-omics; systems biology

DOI:  https://doi.org/10.1016/j.molmet.2023.101857
Metabolism. 2023 Dec 26. pii: S0026-0495(23)00372-4. [Epub ahead of print] 155768

Impact of fasting on the AMPK and PGC-1α axis in rodent and human skeletal muscle: A systematic review.

K L Storoschuk, D Lesiuk, J Nuttall, M LeBouedec, A Khansari, H Islam, B J Gurd.

  Based primarily on evidence from rodent models fasting is currently believed to improve metabolic health in via activation of the AMPK-PGC-1α axis in skeletal muscle. However, it is unclear whether the skeletal muscle AMPK-PGC-1α axis is activated by fasting in humans. The current systematic review examined the fasting response in skeletal muscle from 34 selected studies (7 human, 21 mouse, and 6 rat). From these studies, we gathered 38 unique data points related to AMPK and 47 related to PGC-1α. In human studies, fasting mediated activation of the AMPK-PGC-1α axis is largely absent. Although evidence does support fasting-induced activation of the AMPK-PGC-1α axis in rodent skeletal muscle, the evidence is less robust than anticipated. Our findings question the ability of fasting to activate the AMPK-PGC-1α axis in human skeletal muscle and suggest that the metabolic benefits of fasting in humans are associated with caloric restriction rather than the induction of mitochondrial biogenesis. Registration: https://doi.org/10.17605/OSF.IO/KWNQY.

Keywords:  AMPK; Fasting; Mitochondrial biogenesis; PGC-1α

DOI:  https://doi.org/10.1016/j.metabol.2023.155768
J Cell Sci. 2023 Dec 15. pii: jcs261200. [Epub ahead of print]136(24):

The muscle stem cell niche at a glance.

Margaret Hung, Hsiao-Fan Lo, Grace E L Jones, Robert S Krauss.

  Skeletal muscle stem cells (MuSCs, also called satellite cells) are the source of the robust regenerative capability of this tissue. The hallmark property of MuSCs at homeostasis is quiescence, a reversible state of cell cycle arrest required for long-term preservation of the stem cell population. MuSCs reside between an individual myofiber and an enwrapping basal lamina, defining the immediate MuSC niche. Additional cell types outside the basal lamina, in the interstitial space, also contribute to niche function. Quiescence is actively maintained by multiple niche-derived signals, including adhesion molecules presented from the myofiber surface and basal lamina, as well as soluble signaling factors produced by myofibers and interstitial cell types. In this Cell Science at a Glance article and accompanying poster, we present the most recent information on how niche signals promote MuSC quiescence and provide perspectives for further research.

Keywords:  Cell adhesion; Cell signaling; Muscle; Muscle stem cell; Quiescence; Stem cell niche

DOI:  https://doi.org/10.1242/jcs.261200
J Physiol. 2023 Dec 28.

Combination of chemotherapy and antioxidants: promising therapeutic strategies for muscle atrophy during cancer treatment.

Izabela Monteiro de Araujo, Daniel Dos Santos Dias, Fernanda Silva Carneiro.



Keywords:  antioxidants; cancer; muscle atrophy

DOI:  https://doi.org/10.1113/JP285792
Front Physiol. 2023 ;14 1267456

The epigenetic regulatory effect of histone acetylation and deacetylation on skeletal muscle metabolism-a review.

Junjie Xu, Chenglong Li, Xiaolong Kang.

  Skeletal muscles, the largest organ responsible for energy metabolism in most mammals, play a vital role in maintaining the body's homeostasis. Epigenetic modification, specifically histone acetylation, serves as a crucial regulatory mechanism influencing the physiological processes and metabolic patterns within skeletal muscle metabolism. The intricate process of histone acetylation modification involves coordinated control of histone acetyltransferase and deacetylase levels, dynamically modulating histone acetylation levels, and precisely regulating the expression of genes associated with skeletal muscle metabolism. Consequently, this comprehensive review aims to elucidate the epigenetic regulatory impact of histone acetylation modification on skeletal muscle metabolism, providing invaluable insights into the intricate molecular mechanisms governing epigenetic modifications in skeletal muscle metabolism.

Keywords:  deacetylation; epigenetic modification; histone acetylation; muscle metabolism; skeletal muscle

DOI:  https://doi.org/10.3389/fphys.2023.1267456
J Physiol. 2023 Dec 27.

Age-related changes of skeletal muscle metabolic response to contraction are also sex-dependent.

Madison C Garibotti, Shahrzad Khajehzadehshoushtar, Nathaniel J Andrews, Rohin Malekzadeh.



Keywords:  SS-31; aging; elamipretide (ELAM); fatigue; high intensity interval stimulation (HII); low intensity interval stimulation (LISS); metabolomics; mitochondria; muscle; reactive oxygen species (ROS)

DOI:  https://doi.org/10.1113/JP285736
Biochem Biophys Res Commun. 2023 Dec 20. pii: S0006-291X(23)01507-3. [Epub ahead of print]694 149413

Role of PPARα in inflammatory response of C2C12 myotubes.

Yuki Shimizu, Keiko Hamada, Tingting Guo, Chie Hasegawa, Yusuke Kuga, Katsushi Takeda, Takashi Yagi, Hiroyuki Koyama, Hiroshi Takagi, Daisuke Aotani, Hiromi Kataoka, Tomohiro Tanaka.

  Recent studies have shown a role of inflammation in muscle atrophy and sarcopenia. However, no anti-inflammatory pharmacotherapy has been established for the treatment of sarcopenia. Here, we investigate the potential role of PPARα and its ligands on inflammatory response and PGC-1α gene expression in LPS-treated C2C12 myotubes. Knockdown of PPARα, whose expression was upregulated upon differentiation, augmented IL-6 or TNFα gene expression. Conversely, PPARα overexpression or its activation by ligands suppressed 2-h LPS-induced cytokine expression, with pemafibrate attenuating NF-κB or STAT3 phosphorylation. Of note, reduction of PGC-1α gene expression by LPS treatment for 24 hours was partially reversed by fenofibrate. Our data demonstrate a critical inhibitory role of PPARα in inflammatory response of C2C12 myotubes and suggest a future possibility of PPARα ligands as a candidate for anti-inflammatory therapy against sarcopenia.

Keywords:  Inflammation; PGC-1α; PPAR; Pemafibrate; Sarcopenia; Skeletal muscle

DOI:  https://doi.org/10.1016/j.bbrc.2023.149413
Adv Biol (Weinh). 2023 Dec 27. e2300573

Increased Expression of MiRNA-1 Contributes to Hypobaric Hypoxia-Induced Skeletal Muscle Loss.

Sukanya Srivastava, Samrita Mondal, Richa Rathor, Swati Srivastava, Geetha Suryakumar.

  The present study aims to analyze the role of microRNA-1 in the regulation of skeletal muscle loss under hypobaric hypoxia (HH). Male Sprague Dawley rats (n = 10) weighing 230-250 g are divided into two groups, control and HH exposure for 7 days at 25 000 ft. After the hypoxia exposure, the animals are sacrificed and hindlimb skeletal muscles are excised for further analysis. Studies found the potential role of miR-1 (myomiR) as a biomarker under different atrophic conditions. Prolonged exposure to HH leads to enhanced expression of miR-1 in skeletal muscle as compared to unexposed controls. The Bioinformatics approach is used to identify the validated targets and the biological processes of miR-1. The target prediction tools identify PAX3 and HSP70 as major targets for miR-1. Exposure to HH significantly reduces PAX3 and HSP70 expression during 7 days of HH exposure, which further enhances the activity of FOXO3, MSTN, and ATROGIN known for the progression of skeletal muscle atrophy in relation to control rats. This study indicates the increased expressions of miR-1 and reduced expression of PAX3 and HSP70 lead to impaired myogenesis in skeletal muscle under HH. Further, enhanced expression of muscle degradation genes such as FOXO3, MSTN, and ATROGIN under HH exposure causes skeletal muscle protein loss.

Keywords:  hypobaric hypoxia; microRNA-1; myogenesis, myomiR; skeletal muscle atrophy

DOI:  https://doi.org/10.1002/adbi.202300573
Elife. 2023 Dec 27. pii: RP87340. [Epub ahead of print]12

Mitochondrial electron transport chain, ceramide, and coenzyme Q are linked in a pathway that drives insulin resistance in skeletal muscle.

Alexis Diaz-Vegas, Søren Madsen, Kristen C Cooke, Luke Carroll, Jasmine X Y Khor, Nigel Turner, Xin Y Lim, Miro A Astore, Jonathan C Morris, Anthony S Don, Amanda Garfield, Simona Zarini, Karin A Zemski Berry, Andrew P Ryan, Bryan C Bergman, Joseph T Brozinick, David E James, James G Burchfield.

  Insulin resistance (IR) is a complex metabolic disorder that underlies several human diseases, including type 2 diabetes and cardiovascular disease. Despite extensive research, the precise mechanisms underlying IR development remain poorly understood. Previously we showed that deficiency of coenzyme Q (CoQ) is necessary and sufficient for IR in adipocytes and skeletal muscle (Fazakerley et al., 2018). Here, we provide new insights into the mechanistic connections between cellular alterations associated with IR, including increased ceramides, CoQ deficiency, mitochondrial dysfunction, and oxidative stress. We demonstrate that elevated levels of ceramide in the mitochondria of skeletal muscle cells result in CoQ depletion and loss of mitochondrial respiratory chain components, leading to mitochondrial dysfunction and IR. Further, decreasing mitochondrial ceramide levels in vitro and in animal models (mice, C57BL/6J) (under chow and high-fat diet) increased CoQ levels and was protective against IR. CoQ supplementation also rescued ceramide-associated IR. Examination of the mitochondrial proteome from human muscle biopsies revealed a strong correlation between the respirasome system and mitochondrial ceramide as key determinants of insulin sensitivity. Our findings highlight the mitochondrial ceramide-CoQ-respiratory chain nexus as a potential foundation of an IR pathway that may also play a critical role in other conditions associated with ceramide accumulation and mitochondrial dysfunction, such as heart failure, cancer, and aging. These insights may have important clinical implications for the development of novel therapeutic strategies for the treatment of IR and related metabolic disorders.

Keywords:  biochemistry; cell biology; ceramides; chemical biology; coenzyme Q; human; insulin resistance; mitochondria; mouse; muscle; rat

DOI:  https://doi.org/10.7554/eLife.87340
Geroscience. 2023 Dec 28.

Association of skeletal muscle oxidative capacity with muscle function, sarcopenia-related exercise performance, and intramuscular adipose tissue in older adults.

Akito Yoshiko, Kana Shiozawa, Shiori Niwa, Hideyuki Takahashi, Teruhiko Koike, Kohei Watanabe, Keisho Katayama, Hiroshi Akima.

  Muscle function and exercise performance measures, such as muscle endurance capacity, maximal strength, chair stand score, gait speed, and Timed Up and Go score, are evaluated to diagnose sarcopenia and frailty in older individuals. Furthermore, intramuscular adipose tissue (IntraMAT) content increases with age. Skeletal muscle oxidative capacity determines muscle metabolism and maintains muscle performance. This study aimed to investigate the association of skeletal muscle oxidative capacity with muscle function, exercise performance, and IntraMAT content in older individuals. Thirteen older men and women participated in this study. Skeletal muscle oxidative capacity was assessed by the recovery speed of muscle oxygen saturation after exercise using near-infrared spectroscopy from the medial gastrocnemius. We assessed two muscle functions, peak torque and time to task failure, and four sarcopenia-related exercise performances: handgrip strength, gait speed, 30-s chair stand, and Timed Up and Go. The IntraMAT content was measured using axial magnetic resonance imaging. The results showed a relationship between skeletal muscle oxidative capacity and gait speed but not with muscle functions and other exercise performance measures. Skeletal muscle oxidative capacity was not related to IntraMAT content. Skeletal muscle oxidative capacity, which may be indicative of the capacity of muscle energy production in the mitochondria, is related to locomotive functions but not to other functional parameters or skeletal fat infiltration.

Keywords:  Intramuscular adipose tissue; Muscle endurance function; Muscle oxidative capacity; Physical dysfunction

DOI:  https://doi.org/10.1007/s11357-023-01043-6
Am J Physiol Cell Physiol. 2023 Dec 25.

Potentiation of force by extracellular potassium is not dependent on muscle length in mouse EDL muscle.

Angelos Angelidis, Kristian Overgaard, Rene Vandenboom.

  Increases in myofiber extracellular potassium with prolonged contractile activity can potentiate twitch force. Activity-dependent potentiation, another mechanism of force increase in skeletal muscle, has a strong dependence on muscle or sarcomere length. Thus, potassium-mediated twitch potentiation could also be length-dependent. However, this has not been previously investigated. To this end, we used isolated C57BL/6 mouse extensor digitorum longus (EDL) muscles and elicited twitches at 0.9 Lo, Lo and 1.1 Lo (Lo refers to optimal length) in normal (5 mM) and high (10 mM) potassium solutions. Potentiation magnitude was similar to previous observations and was not significantly different between lengths (0.9 Lo: 12.3 ± 4.4 %, Lo: 12.2 ± 3.6 %, 1.1 Lo: 11.8 ± 4.8 %, values are mean ± SD). Exposure to dantrolene sodium, a compound that attenuates calcium release, reduced twitch force across lengths by ~70%. When dantrolene-affected muscles were subsequently exposed to high potassium, potentiation was not significantly different than in the absence of the former. In total, these findings provide novel information on potassium-mediated twitch potentiation.

Keywords:  elevated extracellular potassium; force potentiation; muscle length; skeletal muscle

DOI:  https://doi.org/10.1152/ajpcell.00456.2023
J Gerontol A Biol Sci Med Sci. 2023 Dec 27. pii: glad283. [Epub ahead of print]

Skeletal muscle energetics explain the sex disparity in mobility impairment in the Study of Muscle, Mobility and Aging (SOMMA).

Philip A Kramer, Paul M Coen, Peggy M Cawthon, Giovanna Distefano, Steven R Cummings, Bret H Goodpaster, Russell T Hepple, Stephen B Kritchevsky, Eric G Shankland, David J Marcinek, Frederico G S Toledo, Kate A Duchowny, Sofhia V Ramos, Stephanie Harrison, Anne B Newman, Anthony J A Molina.

  The age-related decline in muscle mitochondrial energetics contributes to the loss of mobility in older adults. Women experience a higher prevalence of mobility impairment compared to men, but it is unknown whether sex-specific differences in muscle energetics underlie this disparity. In the Study of Muscle, Mobility and Aging (SOMMA), muscle energetics were characterized using in vivo phosphorus-31 magnetic resonance spectroscopy and high-resolution respirometry of vastus lateralis biopsies in 773 participants (56.4% women, age 70-94 years). A Short Physical Performance Battery score ≤ 8 was used to define lower-extremity mobility impairment. Muscle mitochondrial energetics were lower in women compared to men (e.g. Maximal Complex I&II OXPHOS: Women=55.06 +/- 15.95; Men=65.80 +/- 19.74; p<0.001) and in individuals with mobility impairment compared to those without (e.g., Maximal Complex I&II OXPHOS in women: SPPB≥9=56.59 +/- 16.22; SPPB≤8=47.37 +/- 11.85; p<0.001). Muscle energetics were negatively associated with age only in men (e.g., Maximal ETS capacity: R=-0.15, p=0.02; age/sex interaction, p=0.04), resulting in muscle energetics measures that were significantly lower in women than men in the 70-79 age group but not the 80+ age group. Similarly, the odds of mobility impairment were greater in women than men only in the 70-79 age group (70-79 age group, ORage-adjusted=1.78, 95% CI=1.03, 3.08, p=0.038; 80+ age group, ORage-adjusted=1.05, 95% CI=0.52, 2.15, p=0.89). Accounting for muscle energetics attenuated up to 75% of the greater odds of mobility impairment in women. Women had lower muscle mitochondrial energetics compared to men, which largely explain their greater odds of lower-extremity mobility impairment.

Keywords:  Mitochondria; bioenergetics; disability; gender; lower-extremity

DOI:  https://doi.org/10.1093/gerona/glad283
J Cell Mol Med. 2023 Dec 27.

Effects of resistance training on alleviating hypoxia-induced muscle atrophy: Focus on acetylation of FoxO1.

Pengyu Fu, Rongxin Zhu, Weiyang Gao, Lijing Gong.

  This study aims to explore the role of FoxO1 and its acetylation in the alleviation of hypoxia-induced muscle atrophy by resistance training. Forty male Sprague-Dawley rats were randomly divided into four groups: normoxic control group (C), normoxic resistance training group (R), hypoxic control group (H) and hypoxic resistance training group (HR). Rats in R and HR groups were trained on an incremental weight-bearing ladder every other day, while those in H and HR groups were kept in an environment containing 12.4% O2 . After 4 weeks, muscles were collected for analysis. Differentiated L6 myoblasts were analysed in vitro after hypoxia exposure and plasmids transfection (alteration in FoxO1 acetylation). The lean body mass loss, wet weight and fibre cross-sectional area of extensor digitorum longus of rats were decreased after 4 weeks hypoxia, and the adverse reactions above was reversed by resistance training. At the same time, the increase in hypoxia-induced autophagy was suppressed, which was accompanied by a decrease in the expression of nuclear FoxO1 and cytoplasmic Ac-FoxO1 by resistance training. The L6 myotube diameter increased and the expression of autophagic proteins were inhibited under hypoxia via intervening by FoxO1 deacetylation. Overall, resistance training alleviates hypoxia-induced muscle atrophy by inhibiting nuclear FoxO1 and cytoplasmic Ac-FoxO1-mediated autophagy.

Keywords:  acetyl-FoxO1; autophagy; hypoxia; muscle atrophy; resistance training

DOI:  https://doi.org/10.1111/jcmm.18096