bims-moremu 2023-04-23 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2023–04–23
thirty-one papers selected by
Anna Vainshtein, Craft Science Inc.

Enveloped viruses pseudotyped with mammalian myogenic cell fusogens target skeletal muscle for gene delivery.
A novel method for visualizing in-vivo rates of protein degradation provides insight into how TRIM28 regulates muscle size.
Multimodal high-resolution nano-DESI MSI and immunofluorescence imaging reveal molecular signatures of skeletal muscle fiber types.
The elusive role of myostatin signaling for muscle regeneration and maintenance of muscle and bone homeostasis.
Age-associated inflammation and implications for skeletal muscle responses to exercise.
Skeletal muscle insulin resistance.
Age and low intensity resistance exercise on exosome-like vesicle and skeletal muscle miRNA profiles.
Targeted regulation of TAK1 counteracts dystrophinopathy in a DMD mouse model.
AMPK is mitochondrial medicine for neuromuscular disorders.
A chronic high-fat diet does not exacerbate muscle atrophy in fast-twitch skeletal muscle of aged mice.
TBC1D4-S711 controls skeletal muscle insulin sensitization after exercise and contraction.
Microtubule-mediated GLUT4 trafficking is disrupted in insulin resistant skeletal muscle.
Pleiotropic and multi-systemic actions of physical exercise on PGC-1α signaling during the aging process.
Exercise reprograms the inflammatory landscape of multiple stem cell compartments during mammalian aging.
Pro-inflammatory macrophages impair skeletal muscle regeneration in ischemic-damaged limbs by inducing precocious differentiation of satellite cells.
Lunar gravity prevents skeletal muscle atrophy but not myofiber type shift in mice.
Acute changes in serum and skeletal muscle steroids in resistance-trained men.
Exogenous ketosis elevates circulating erythropoietin and stimulates muscular angiogenesis during endurance training overload.
Influence of aspirin on aging skeletal muscle: Insights from a cross-sectional cohort of septuagenarians.
Aerobic exercise reduced the amount of CHRONO bound to BMAL1 and ameliorated glucose metabolic dysfunction in skeletal muscle of high-fat diet-fed mice.
Role of the Osteocyte in Musculoskeletal Disease.
Distinct microRNA and protein profiles of extracellular vesicles secreted from myotubes from morbidly obese donors with type 2 diabetes in response to electrical pulse stimulation.
Resistance Training Diminishes Mitochondrial Adaptations to Subsequent Endurance Training.
MYH7 in cardiomyopathy and skeletal muscle myopathy.
Effects of exercise training on glucocorticoid-induced muscle atrophy: literature review.
Pyruvate-supported flux through medium-chain ketothiolase promotes mitochondrial lipid tolerance in cardiac and skeletal muscles.
Deletion of quinolinate phosphoribosyltransferase gene accelerates frailty phenotypes and neuromuscular decline with aging in a sex-specific pattern.
Degeneration of muscle spindles in a murine model of Pompe disease.
Improvement of muscle strength in specific muscular regions in nusinersen-treated adult patients with 5q-spinal muscular atrophy.
Single-cell transcriptomic analysis uncovers diverse and dynamic senescent cell populations.
How can we modulate aging through nutrition and physical exercise? An epigenetic approach.

Cell. 2023 Apr 12. pii: S0092-8674(23)00330-6. [Epub ahead of print]

Enveloped viruses pseudotyped with mammalian myogenic cell fusogens target skeletal muscle for gene delivery.

Sajedah M Hindi, Michael J Petrany, Elena Greenfeld, Leah C Focke, Alyssa A W Cramer, Michael A Whitt, Ramzi J Khairallah, Christopher W Ward, Jeffrey S Chamberlain, Benjamin Podbilewicz, Vikram Prasad, Douglas P Millay.

  Entry of enveloped viruses into cells is mediated by viral fusogenic proteins that drive membrane rearrangements needed for fusion between viral and target membranes. Skeletal muscle development also requires membrane fusion events between progenitor cells to form multinucleated myofibers. Myomaker and Myomerger are muscle-specific cell fusogens but do not structurally or functionally resemble classical viral fusogens. We asked whether the muscle fusogens could functionally substitute for viral fusogens, despite their structural distinctiveness, and fuse viruses to cells. We report that engineering of Myomaker and Myomerger on the membrane of enveloped viruses leads to specific transduction of skeletal muscle. We also demonstrate that locally and systemically injected virions pseudotyped with the muscle fusogens can deliver μDystrophin to skeletal muscle of a mouse model of Duchenne muscular dystrophy and alleviate pathology. Through harnessing the intrinsic properties of myogenic membranes, we establish a platform for delivery of therapeutic material to skeletal muscle.

Keywords:  cell fusion; gene therapy; muscular dystrophy; myomaker; myomerger/myomixer; viral pseudotyping

DOI:  https://doi.org/10.1016/j.cell.2023.03.033
iScience. 2023 Apr 21. 26(4): 106526

A novel method for visualizing in-vivo rates of protein degradation provides insight into how TRIM28 regulates muscle size.

Nathaniel D Steinert, Kent W Jorgenson, Kuan-Hung Lin, Jake B Hermanson, Jake L Lemens, Troy A Hornberger.

  Skeletal muscle size is controlled by the balance between protein synthesis and protein degradation. Given the essential role of skeletal muscle in maintaining a high quality of life, understanding the mechanisms that modulate this balance are of critical importance. Previously, we demonstrated that muscle-specific knockout of TRIM28 reduces muscle size and function and in the current study, we discovered that this effect is associated with an increase in protein degradation and a dramatic reduction in the expression of Mettl21c. Importantly, we also determined that overexpression of Mettl21c is sufficient to induce hypertrophy in both control and TRIM28 knockout muscles. Moreover, we developed a simple pulse-chase biorthogonal non-canonical amino acid tagging technique that enabled us to visualize the in vivo rate of protein degradation, and with this technique were able to conclude that the hypertrophic effect of Mettl21c is due, at least in part, to an inhibition of protein degradation.

Keywords:  Biochemistry; Cell biology; Developmental biology

DOI:  https://doi.org/10.1016/j.isci.2023.106526
Chem Sci. 2023 Apr 12. 14(15): 4070-4082

Multimodal high-resolution nano-DESI MSI and immunofluorescence imaging reveal molecular signatures of skeletal muscle fiber types.

Daisy Unsihuay, Hang Hu, Jiamin Qiu, Alessandra Latorre-Palomino, Manxi Yang, Feng Yue, Ruichuan Yin, Shihuan Kuang, Julia Laskin.

The skeletal muscle is a highly heterogeneous tissue comprised of different fiber types with varying contractile and metabolic properties. The complexity in the analysis of skeletal muscle fibers associated with their small size (30-50 μm) and mosaic-like distribution across the tissue tnecessitates the use of high-resolution imaging to differentiate between fiber types. Herein, we use a multimodal approach to characterize the chemical composition of skeletal fibers in a limb muscle, the gastrocnemius. Specifically, we combine high-resolution nanospray desorption electrospray ionization (nano-DESI) mass spectrometry imaging (MSI) with immunofluorescence (IF)-based fiber type identification. Computational image registration and segmentation approaches are used to integrate the information obtained with both techniques. Our results indicate that the transition between oxidative and glycolytic fibers is associated with shallow chemical gradients (<2.5 fold change in signals). Interestingly, we did not find any fiber type-specific molecule. We hypothesize that these findings might be linked to muscle plasticity thereby facilitating a switch in the metabolic properties of fibers in response to different conditions such as exercise and diet, among others. Despite the shallow chemical gradients, cardiolipins (CLs), acylcarnitines (CAR), monoglycerides (MGs), fatty acids, highly polyunsaturated phospholipids, and oxidized phospholipids, were identified as molecular signatures of oxidative metabolism. In contrast, histidine-related compounds were found as molecular signatures of glycolytic fibers. Additionally, the presence of highly polyunsaturated acyl chains in phospholipids was found in oxidative fibers whereas more saturated acyl chains in phospholipids were found in glycolytic fibers which suggests an effect of the membrane fluidity on the metabolic properties of skeletal myofibers.

DOI: https://doi.org/10.1039/d2sc06020e
Osteoporos Sarcopenia. 2023 Mar;9(1): 1-7

The elusive role of myostatin signaling for muscle regeneration and maintenance of muscle and bone homeostasis.

Akash Mitra, Rizwan Qaisar, Bipasha Bose, Shenoy P Sudheer.

  Skeletal muscle is one of the leading frameworks of the musculo-skeletal system, which works in synergy with the bones. Long skeletal muscles provide stability and mobility to the human body and are primarily composed of proteins. Conversely, improper functioning of various skeletal muscles leads to diseases and disorders, namely, age-related muscle disorder called sarcopenia, a group of genetic muscle disorders such as muscular dystrophies, and severe muscle wasting in cancer known as cachexia. However, skeletal muscle has an excellent ability to undergo hypertrophy and enhanced functioning during sustained exercise over time. Indeed, these processes of skeletal muscle regeneration/hypertrophy, as well as degeneration and atrophy, involve an interplay of various signaling pathways. Myostatin is one such chemokine/myokine with a significant contribution to muscle regeneration or atrophy in multiple conditions. In this review, we try to put together the role and regulation of myostatin as a function of muscle regeneration extrapolated to multiple aspects of its molecular functions.

Keywords:  Atrophy; Muscle; Muscle degeneration; Myostatin

DOI:  https://doi.org/10.1016/j.afos.2023.03.008
Exp Gerontol. 2023 Apr 19. pii: S0531-5565(23)00098-0. [Epub ahead of print] 112177

Age-associated inflammation and implications for skeletal muscle responses to exercise.

Hawley E Kunz, Ian R Lanza.

  Aging is associated with profound alterations in skeletal muscle, including loss of muscle mass and function, local inflammation, altered mitochondrial physiology, and attenuated anabolic responses to exercise termed anabolic resistance. "Inflammaging," the chronic, low-grade inflammation associated with aging, may contribute to many of the age-related derangements in skeletal muscle, including its ability to respond to exercise and nutritional stimuli. Inflammation and exercise are closely intertwined in numerous ways. A single bout of muscle-damaging exercise stimulates an acute inflammatory response in the skeletal muscle that is essential for muscle repair and regeneration; however, the chronic systemic and local inflammation associated with aging may impair acute inflammatory and anabolic responses to exercise. In contrast, exercise training is anti-inflammatory, targeting many of the potential root causes of inflammaging. In this review, we discuss the interplay between inflammation and exercise in aging and highlight potential therapeutic targets for improving adaptive responses to exercise in older adults.

Keywords:  Aging; Exercise; Inflammation; Skeletal muscle

DOI:  https://doi.org/10.1016/j.exger.2023.112177
J Physiol. 2023 Apr 18.

Skeletal muscle insulin resistance.

James Smorenburg, Patrick McTavish, Giulia Kobylnik.



Keywords:  DAGs; PKC; ceramides; inflammation; insulin resistance; muscle fibers; skeletal muscle

DOI:  https://doi.org/10.1113/JP284721
J Physiol. 2023 Apr 22.

Age and low intensity resistance exercise on exosome-like vesicle and skeletal muscle miRNA profiles.

Aaron Wang.



Keywords:  aging; exercise; exosome; exosome-like vesicle; microRNA; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.1113/JP284547
JCI Insight. 2023 Apr 18. pii: e164768. [Epub ahead of print]

Targeted regulation of TAK1 counteracts dystrophinopathy in a DMD mouse model.

Anirban Roy, Tatiana E Koike, Aniket S Joshi, Meiricris Tomaz da Silva, Kavya Mathukumalli, Mingfu Wu, Ashok Kumar.

  Muscular dystrophies are a group of genetic neuromuscular disorders that involve severe muscle wasting. Transforming growth factor β-activated kinase 1 (TAK1) is an important signaling protein that regulates cell survival, growth, and inflammation. TAK1 has been recently found to promote myofiber growth in the skeletal muscle of adult mice. However, the role of TAK1 in muscle diseases remains poorly understood. In the present study, we have investigated how TAK1 affects the progression of dystrophic phenotype in the mdx mouse model of Duchenne muscular dystrophy (DMD). TAK1 is highly activated in the dystrophic muscle of mdx mice during the peak necrotic phase. While targeted inducible inactivation of TAK1 inhibits myofiber injury in young mdx mice, it results in reduced muscle mass and contractile function. TAK1 inactivation also causes loss of muscle mass in adult mdx mice. By contrast, forced activation of TAK1 through overexpression of TAK1 and TAB1 induces myofiber growth without having any deleterious effect on muscle histopathology. Collectively, our results suggest that TAK1 is a positive regulator of skeletal muscle mass and targeted regulation of TAK1 can suppress myonecrosis and ameliorate disease progression in DMD. .

Keywords:  Muscle; Muscle Biology; Signal transduction; Skeletal muscle; Therapeutics

DOI:  https://doi.org/10.1172/jci.insight.164768
Trends Mol Med. 2023 Apr 19. pii: S1471-4914(23)00070-9. [Epub ahead of print]

AMPK is mitochondrial medicine for neuromuscular disorders.

Andrew I Mikhail, Sean Y Ng, Stephanie R Mattina, Vladimir Ljubicic.

  Duchenne muscular dystrophy (DMD), myotonic dystrophy type 1 (DM1), and spinal muscular atrophy (SMA) are the most prevalent neuromuscular disorders (NMDs) in children and adults. Central to a healthy neuromuscular system are the processes that govern mitochondrial turnover and dynamics, which are regulated by AMP-activated protein kinase (AMPK). Here, we survey mitochondrial stresses that are common between, as well as unique to, DMD, DM1, and SMA, and which may serve as potential therapeutic targets to mitigate neuromuscular disease. We also highlight recent advances that leverage a mutation-agnostic strategy featuring physiological or pharmacological AMPK activation to enhance mitochondrial health in these conditions, as well as identify outstanding questions and opportunities for future pursuit.

Keywords:  Duchenne muscular dystrophy; mitophagy; myotonic dystrophy type 1; skeletal muscle; spinal muscular atrophy

DOI:  https://doi.org/10.1016/j.molmed.2023.03.008
Exp Physiol. 2023 Apr 19.

A chronic high-fat diet does not exacerbate muscle atrophy in fast-twitch skeletal muscle of aged mice.

Tsutomu Tagawa, Hiroaki Eshima, Saori Kakehi, Ryuzo Kawamori, Hirotaka Watada, Yoshifumi Tamura.

   NEW FINDINGS: What is the central question of this study? Ageing leads to a loss of mass in skeletal muscle, but the effect of obesity on ageing-related muscle wasting is unclear. In this study, we aimed to demonstrate the specific effect of obesity on fast-twitch skeletal muscle in ageing. What is the main finding and its importance? Our findings show that the obesity induced by long-term ingestion of a high-fat diet does not aggravate muscle wasting in fast-twitch skeletal muscle of aged mice, indicating that the present study provides morphological characteristics for skeletal muscle of sarcopenic obesity.
ABSTRACT: Obesity and ageing reduce muscle mass and lead to deficits in muscle maintenance, but it is not known whether obesity accelerates muscle wasting additively in the setting of ageing. We investigated morphological characteristics in fast-twitch extensor digitorum longus (EDL) muscle of mice fed a low-fat diet (LFD) or a high-fat diet (HFD) for 4 or 20 months. The fast-twitch EDL muscle was harvested, and the muscle fibre-type composition, individual muscle cross-sectional area and myotube diameter were measured. We found an increase in the percentage of type IIa and IIx myosin heavy chain fibres in the whole EDL muscle, but a decrease in type IIB myosin heavy chain in both HFD protocols. The cross-sectional area and myofibre diameter were lower in both groups of aged mice (after 20 months of LFD or HFD) compared with young mice (after 4 months of the diets), but there were no differences between mice fed LFD or HFD for 20 months. These data suggest that long-term feeding of HFD does not aggravate muscle wasting in fast-twitch EDL muscle of male mice.

Keywords:  ageing; cross-sectional area; fast-twitch muscle; high-fat diet; myofibre diameter; skeletal muscle

DOI:  https://doi.org/10.1113/EP091106
Diabetes. 2023 Apr 19. pii: db220666. [Epub ahead of print]

TBC1D4-S711 controls skeletal muscle insulin sensitization after exercise and contraction.

Rasmus Kjøbsted, Jonas M Kristensen, Nicolas O Eskesen, Kohei Kido, Klara Fjorder, Ditte F Damgaard, Jeppe K Larsen, Nicoline R Andersen, Jesper B Birk, Anders Gudiksen, Jonas T Treebak, Peter Schjerling, Henriette Pilegaard, Jørgen F P Wojtaszewski.

The ability of insulin to stimulate glucose uptake in skeletal muscle is important for whole-body glycemic control. Insulin-stimulated skeletal muscle glucose uptake is improved in the period after a single bout of exercise and accumulating evidence suggests that phosphorylation of TBC1D4 by the protein kinase AMPK is the primary mechanism responsible for this phenomenon. To investigate this, we generated a TBC1D4 knock-in mouse model with a serine-to-alanine point mutation at residue 711 that is phosphorylated in response to both insulin and AMPK activation. Female TBC1D4-S711A mice exhibited normal growth and eating behavior as well as intact wholebody glycemic control on chow and high-fat diets. Moreover, muscle contraction increased glucose uptake, glycogen utilization and AMPK activity similarly in wild-type and TBC1D4-S711A mice. In contrast, improvements in whole-body and muscle insulin sensitivity after exercise and contractions were only evident in wild-type mice and occurred concomitantly with enhanced phosphorylation of TBC1D4-S711. These results provide genetic evidence to support that TBC1D4-S711 serves as a major point of convergence for AMPK- and insulin-induced signaling that mediates the insulin-sensitizing effect of exercise and contractions on skeletal muscle glucose uptake.

DOI: https://doi.org/10.2337/db22-0666
Elife. 2023 Apr 19. pii: e83338. [Epub ahead of print]12

Microtubule-mediated GLUT4 trafficking is disrupted in insulin resistant skeletal muscle.

Jonas R Knudsen, Kaspar W Persson, Carlos Henriquez-Olguin, Zhencheng Li, Nicolas Di Leo, Sofie A Hesselager, Steffen H Raun, Janne R Hingst, Raphaël Trouillon, Martin Wohlwend, Jørgen F P Wojtaszewski, Martin A M Gijs, Thomas Elbenhardt Jensen.

  Microtubules serve as tracks for long-range intracellular trafficking of glucose transporter 4 (GLUT4), but the role of this process in skeletal muscle and insulin resistance is unclear. Here, we used fixed and live-cell imaging to study microtubule-based GLUT4 trafficking in human and mouse muscle fibers and L6 rat muscle cells. We found GLUT4 localized on the microtubules in mouse and human muscle fibers. Pharmacological microtubule disruption using Nocodazole (Noco) prevented long-range GLUT4 trafficking and depleted GLUT4-enriched structures at microtubule nucleation sites in a fully reversible manner. Using a perifused muscle-on-a-chip system to enable real-time glucose uptake measurements in isolated mouse skeletal muscle fibers, we observed that Noco maximally disrupted the microtubule network after 5 min without affecting insulin-stimulated glucose uptake. In contrast, a 2h Noco treatment markedly decreased insulin responsiveness of glucose uptake. Insulin resistance in mouse muscle fibers induced either in vitro by C2 ceramides or in vivo by diet-induced obesity, impaired microtubule-based GLUT4 trafficking. Transient knockdown of the microtubule motor protein kinesin-1 protein KIF5B in L6 muscle cells reduced insulin-stimulated GLUT4 translocation while pharmacological kinesin-1 inhibition in incubated mouse muscles strongly impaired insulin-stimulated glucose uptake. Thus, in adult skeletal muscle fibers, the microtubule network is essential for intramyocellular GLUT4 movement, likely functioning to maintain an insulin-responsive cell-surface recruitable GLUT4 pool via kinesin-1 mediated trafficking.

Keywords:  cell biology; human; mouse; rat

DOI:  https://doi.org/10.7554/eLife.83338
Ageing Res Rev. 2023 Apr 14. pii: S1568-1637(23)00094-6. [Epub ahead of print]87 101935

Pleiotropic and multi-systemic actions of physical exercise on PGC-1α signaling during the aging process.

Ivo Vieira de Sousa Neto, Ana Paula Pinto, Vitor Rosetto Muñoz, Rita de Cássia Marqueti, José Rodrigo Pauli, Eduardo Rochete Ropelle, Adelino Sanchez Ramos da Silva.

  Physical training is a potent therapeutic approach for improving mitochondrial health through peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) signaling pathways. However, comprehensive information regarding the physical training impact on PGC-1α in the different physiological systems with advancing age is not fully understood. This review sheds light on the frontier-of-knowledge data regarding the chronic effects of exercise on the PGC-1α signaling pathways in rodents and humans. We address the molecular mechanisms involved in the different tissues, clarifying the precise biological action of PGC-1α, restricted to the aged cell type. Distinct exercise protocols (short and long-term) and modalities (aerobic and resistance exercise) increase the transcriptional and translational PGC-1α levels in adipose tissue, brain, heart, liver, and skeletal muscle in animal models, suggesting that this versatile molecule induces pleiotropic responses. However, PGC-1α function in some human tissues (adipose tissue, heart, and brain) remains challenging for further investigations. PGC-1α is not a simple transcriptional coactivator but supports a biochemical environment of mitochondrial dynamics, controlling physiological processes (primary metabolism, tissue remodeling, autophagy, inflammation, and redox balance). Acting as an adaptive mechanism, the long-term effects of PGC-1α following exercise may reflect the energy demand to coordinate multiple organs and contribute to cellular longevity.

Keywords:  Age; Metabolism; Mitochondria function; PGC-1α; Physical activity

DOI:  https://doi.org/10.1016/j.arr.2023.101935
Cell Stem Cell. 2023 Apr 13. pii: S1934-5909(23)00087-5. [Epub ahead of print]

Exercise reprograms the inflammatory landscape of multiple stem cell compartments during mammalian aging.

Ling Liu, Soochi Kim, Matthew T Buckley, Jaime M Reyes, Jengmin Kang, Lei Tian, Mingqiang Wang, Alexander Lieu, Michelle Mao, Cristina Rodriguez-Mateo, Heather D Ishak, Mira Jeong, Joseph C Wu, Margaret A Goodell, Anne Brunet, Thomas A Rando.

  Exercise has the ability to rejuvenate stem cells and improve tissue regeneration in aging animals. However, the cellular and molecular changes elicited by exercise have not been systematically studied across a broad range of cell types in stem cell compartments. We subjected young and old mice to aerobic exercise and generated a single-cell transcriptomic atlas of muscle, neural, and hematopoietic stem cells with their niche cells and progeny, complemented by whole transcriptome analysis of single myofibers. We found that exercise ameliorated the upregulation of a number of inflammatory pathways associated with old age and restored aspects of intercellular communication mediated by immune cells within these stem cell compartments. Exercise has a profound impact on the composition and transcriptomic landscape of circulating and tissue-resident immune cells. Our study provides a comprehensive view of the coordinated responses of multiple aged stem cells and niche cells to exercise at the transcriptomic level.

Keywords:  aging; exercise; hematopoietic stem cells; inflammation; muscle stem cells; myofibers; neural stem cells; scRNA-seq; skeletal muscle; subventricular zone

DOI:  https://doi.org/10.1016/j.stem.2023.03.016
bioRxiv. 2023 Apr 03. pii: 2023.04.01.535211. [Epub ahead of print]

Pro-inflammatory macrophages impair skeletal muscle regeneration in ischemic-damaged limbs by inducing precocious differentiation of satellite cells.

Kevin W Southerland, Yueyuan Xu, Derek T Peters, Xiaolin Wei, Xin Lin, Yu Xiang, Kaileen Fei, Lindsey A Olivere, Jeremy M Morowitz, James Otto, Qunsheng Dai, Christopher D Kontos, Yarui Diao.

Chronic limb-threatening ischemia (CLTI), representing the end-stage of peripheral arterial disease (PAD), is associated with a one-year limb amputation rate of âˆ¼15-20% and significant mortality. A key characteristic of CLTI is the failure of the innate regenerative capacity of skeletal muscle, though the underlying mechanisms remain unclear. Here, single-cell transcriptome analysis of ischemic and non-ischemic muscle from the same CLTI patients demonstrated that ischemic-damaged tissue is enriched with pro-inflammatory macrophages. Comparable results were also observed in a murine CLTI model. Importantly, integrated analyses of both human and murine data revealed premature differentiation of muscle satellite cells (MuSCs) in damaged tissue and indications of defects in intercellular signaling communication between MuSCs and their inflammatory niche. Collectively, our research provides the first single-cell transcriptome atlases of skeletal muscle from CLTI patients and murine models, emphasizing the crucial role of macrophages and inflammation in regulating muscle regeneration in CLTI through interactions with MuSCs.

DOI: https://doi.org/10.1101/2023.04.01.535211
Commun Biol. 2023 Apr 21. 6(1): 424

Lunar gravity prevents skeletal muscle atrophy but not myofiber type shift in mice.

Takuto Hayashi, Ryo Fujita, Risa Okada, Michito Hamada, Riku Suzuki, Sayaka Fuseya, James Leckey, Maho Kanai, Yuri Inoue, Shunya Sadaki, Ayano Nakamura, Yui Okamura, Chikara Abe, Hironobu Morita, Tatsuya Aiba, Teruhiro Senkoji, Michihiko Shimomura, Maki Okada, Daisuke Kamimura, Akane Yumoto, Masafumi Muratani, Takashi Kudo, Dai Shiba, Satoru Takahashi.

Skeletal muscle is sensitive to gravitational alterations. We recently developed a multiple artificial-gravity research system (MARS), which can generate gravity ranging from microgravity to Earth gravity (1 g) in space. Using the MARS, we studied the effects of three different gravitational levels (microgravity, lunar gravity [1/6 g], and 1 g) on the skeletal muscle mass and myofiber constitution in mice. All mice survived and returned to Earth, and skeletal muscle was collected two days after landing. We observed that microgravity-induced soleus muscle atrophy was prevented by lunar gravity. However, lunar gravity failed to prevent the slow-to-fast myofiber transition in the soleus muscle in space. These results suggest that lunar gravity is enough to maintain proteostasis, but a greater gravitational force is required to prevent the myofiber type transition. Our study proposes that different gravitational thresholds may be required for skeletal muscle adaptation.

DOI: https://doi.org/10.1038/s42003-023-04769-3
Front Endocrinol (Lausanne). 2023 ;14 1081056

Acute changes in serum and skeletal muscle steroids in resistance-trained men.

Felipe C Vechin, Jakob L Vingren, Guilherme D Telles, Miguel S Conceicao, Cleiton A Libardi, Manoel E Lixandrao, Felipe Damas, Telma F Cunha, Patricia C Brum, Luiz A Riani, Carlos Ugrinowitsch.

   Introduction: Resistance exercise can significantly increase serum steroid concentrations after an exercise bout. Steroid hormones are involved in the regulation of several important bodily functions (e.g., muscle growth) through both systemic delivery and local production. Thus, we aimed to determine whether resistance exercise-induced increases in serum steroid hormone concentrations are accompanied by enhanced skeletal muscle steroid concentrations, or whether muscle contractions per se induced by resistance exercise can increase intramuscular steroid concentrations.
Methods: A counterbalanced, within-subject, crossover design was applied. Six resistance-trained men (26 ± 5 years; 79 ± 8 kg; 179 ± 10 cm) performed a single-arm lateral raise exercise (10 sets of 8 to 12 RM - 3 min rest between sets) targeting the deltoid muscle followed by either squat exercise (10 sets of 8 to 12 RM - 1 min rest) to induce a hormonal response (high hormone [HH] condition) or rest (low hormone [LH] condition). Blood samples were obtained pre-exercise and 15 min and 30 min post-exercise; muscle specimens were harvested pre-exercise and 45 min post-exercise. Immunoassays were used to measure serum and muscle steroids (total and free testosterone, dehydroepiandrosterone sulfate, dihydrotestosterone, and cortisol; free testosterone measured only in serum and dehydroepiandrosterone only in muscle) at these time points.
Results: In the serum, only cortisol significantly increased after the HH protocol. There were no significant changes in muscle steroid concentrations after the protocols.
Discussion: Our study provides evidence that serum steroid concentration increases (cortisol only) seem not to be aligned with muscle steroid concentrations. The lack of change in muscle steroid after protocols suggests that resistance-trained individuals were desensitized to the exercise stimuli. It is also possible that the single postexercise timepoint investigated in this study might be too early or too late to observe changes. Thus, additional timepoints should be examined to determine if RE can indeed change muscle steroid concentrations either by skeletal muscle uptake of these hormones or the intramuscular steroidogenesis process.

Keywords:  intracrine; intracrinology; measurement error; steroidogenesis; strength exercise

DOI:  https://doi.org/10.3389/fendo.2023.1081056
J Physiol. 2023 Apr 16.

Exogenous ketosis elevates circulating erythropoietin and stimulates muscular angiogenesis during endurance training overload.

Chiel Poffé, Ruben Robberechts, Ruud Van Thienen, Peter Hespel.

  De novo capillarization is a primary muscular adaptation to endurance exercise training and is crucial to improve performance. Excess training load, however, impedes such beneficial adaptations, yet we recently demonstrated that such downregulation may be counteracted by ketone ester ingestion (KE) post-exercise. Therefore, we investigated whether KE could increase pro-angiogenic factors and thereby stimulate muscular angiogenesis during a three-week endurance training-overload period involving 10 training sessions/week in healthy, male volunteers. Subjects received either 25g of a ketone ester (KE, n = 9) or a control drink (CON, n = 9) immediately after each training session and before sleep. In KE, but not in CON, the training intervention increased number of capillary contacts and capillary-to-fiber perimeter exchange index by 44% and 42%, respectively. Furthermore, KE also substantially increased VEGF and eNOS expression both at the protein and mRNA level. Serum erythropoietin concentration was concomitantly increased by 26%. Conversely, in CON the training intervention increased only the protein content of eNOS. These data indicate that intermittent exogenous ketosis during endurance overload training stimulates muscular angiogenesis. This likely resulted from a direct stimulation of muscle angiogenesis, which may be at least partly due to stimulation of erythropoietin secretion and elevated VEGF activity, and/or an inhibition of the suppressive effect of overload training on the normal angiogenic response to training. This study provides novel evidence to support the potential of exogenous ketosis to benefit endurance training-induced muscular adaptation. KEY POINTS SUMMARY: Increased capillarization is a primary muscular adaptation to endurance exercise training. However, excess training load may impede such response. We previously observed that intermittent exogenous ketosis by postexercise and pre-sleep ketone ester ingestion (KE) counteracted physiological dysregulations induced by endurance overload training. Therefore, we investigated whether KE could increase pro-angiogenic factors thereby stimulating muscular angiogenesis during a three-week endurance training-overload period. We show that the overload training period in the presence, but not in the absence of KE, markedly increased muscle capillarization (+40%). This increase was accompanied by higher circulating erythropoietin concentration and stimulation of the pro-angiogenic factors VEGF and eNOS in skeletal muscle. Collectively, our data indicate that intermittent exogenous ketosis may evolve as a potent nutritional strategy to facilitate recovery from strenuous endurance exercise, thereby stimulating beneficial muscular adaptations. Abstract figure legend: Eighteen healthy, fit male volunteers were subjected to a 3 week endurance training-overload program. Subjects received either 25g of a ketone ester drink or an isocaloric placebo immediately after each training session and before sleep. The training intervention increased skeletal muscle capillarization in the ketone ester group, but not in the placebo group. The angiogenic response in the ketone ester group was accompanied by an increase in circulating erythropoietin (EPO) concentrations, and stimulation of pro-angiogenic factors in skeletal muscle. These findings indicate that intermittent ketone ester supplementation stimulates beneficial muscular adaptations during strenuous endurance exercise training. This article is protected by copyright. All rights reserved.

Keywords:  EPO; VEGF; angiogenesis; exercise training; ketone

DOI:  https://doi.org/10.1113/JP284346
Physiol Rep. 2023 Apr;11(8): e15669

Influence of aspirin on aging skeletal muscle: Insights from a cross-sectional cohort of septuagenarians.

William A Fountain, Masatoshi Naruse, W Holmes Finch, Alex Claiborne, Scott W Trappe, Todd A Trappe.

  Aspirin is one of the most commonly consumed cyclooxygenase (COX)-inhibitors and anti-inflammatory drugs and has been shown to block COX-produced regulators of inflammation and aging skeletal muscle size. We used propensity score matching to compare skeletal muscle characteristics of individuals from the Health ABC study that did not consume aspirin or any other COX-inhibiting drugs (non-consumers, n = 497, 74 ± 3 year, 168 ± 9 cm, 75.1 ± 13.8 kg, 33.1 ± 7.4% body fat, 37% women, 34% black) to those that consumed aspirin daily (and not any other COX-inhibiting drugs) and for at least 1 year (aspirin consumers, n = 515, 74 ± 3 year, 168 ± 9 cm, 76.2 ± 13.6 kg, 33.8 ± 7.1% body fat, 39% women, 30% black, average aspirin consumption: 6 year). Subjects were matched (p > 0.05) based on age, height, weight, % body fat, sex, and race (propensity scores: 0.33 ± 0.09 vs. 0.33 ± 0.09, p > 0.05). There was no difference between non-consumers and aspirin consumers for computed tomography-determined muscle size of the quadriceps (103.5 ± 0.9 vs. 104.9 ± 0.8 cm2 , p > 0.05) or hamstrings (54.6 ± 0.5 vs. 54.9 ± 0.5 cm2 , p > 0.05), or quadriceps muscle strength (111.1 ± 2.0 vs. 111.7 ± 2.0 Nm, p > 0.05). However, muscle attenuation (i.e., density) was higher in the aspirin consumers in the quadriceps (40.9 ± 0.3 vs. 44.4 ± 0.3 Hounsfield unit [HU], p < 0.05) and hamstrings (27.7 ± 0.4 vs. 33.2 ± 0.4 HU, p < 0.05). These cross sectional data suggest that chronic aspirin consumption does not influence age-related skeletal muscle atrophy, but does influence skeletal muscle composition in septuagenarians. Prospective longitudinal investigations remain necessary to better understand the influence of chronic COX regulation on aging skeletal muscle health.

Keywords:  COX inhibitor; aging; aspirin; inflammation; skeletal muscle

DOI:  https://doi.org/10.14814/phy2.15669
Life Sci. 2023 Apr 13. pii: S0024-3205(23)00330-2. [Epub ahead of print] 121696

Aerobic exercise reduced the amount of CHRONO bound to BMAL1 and ameliorated glucose metabolic dysfunction in skeletal muscle of high-fat diet-fed mice.

Lei Xu, Jie Jia, Shudan Miao, Lijing Gong, Jin Wang, Shiyi He, Ying Zhang.

   AIMS: The purpose of this study was to investigate the effects of aerobic exercise on the CHRONO-BMAL1 pathway and glucose metabolism in skeletal muscle of high-fat diet (HFD)-fed mice.
MAIN METHODS: Male C57BL/6J mice were randomly allocated into four groups: normal chow diet with control (NCD + CON), NCD with exercise (NCD + EXE), HFD with control (HFD + CON) and HFD with exercise (HFD + EXE). The NCD and HFD groups were respectively fed a diet of 10 % and 60 % kilocalories from fat for 12 weeks. During the dietary intervention, EXE groups were subjected to 70 % VO2max intensity of treadmill exercise six times per week for 12 weeks. Body weight, energy intake, fat weight, serum lipid profiles, systemic glucose homeostasis, the amount of CHRONO bound to BMAL1, the enzymatic activity, mRNA and protein expression involved in glucose metabolism of skeletal muscle were measured.
KEY FINDINGS: The results showed that the 12-week HFD feeding without exercise induced weight gain, serum dyslipidemia and insulin resistance. Furthermore, HFD increased the amount of CHRONO bound to BMAL1 and repressed the glucose metabolism in skeletal muscle. However, aerobic exercise prevented weight gain, serum dyslipidemia and systemic insulin resistance in the HFD-fed mice. Meanwhile, aerobic exercise also decreased the amount of CHRONO bound to BMAL1 and increased the glucose uptake, glucose oxidation and glycogenesis in skeletal muscle of the HFD-fed mice.
SIGNIFICANCE: These data suggested that aerobic exercise could counterbalance CHRONO interacted with BMAL1 and prevent glucose metabolism dysfunction of skeletal muscle, and finally maintain whole-body insulin sensitivity in the HFD-fed mice.

Keywords:  Aerobic exercise; CHRONO-BMAL1 pathway; Glucose metabolism of skeletal muscle; High-fat diet; Insulin sensitivity

DOI:  https://doi.org/10.1016/j.lfs.2023.121696
Curr Osteoporos Rep. 2023 Apr 21.

Role of the Osteocyte in Musculoskeletal Disease.

Anika Shimonty, Lynda F Bonewald, Fabrizio Pin.

   PURPOSE OF THE REVIEW: The purpose of this review is to summarize the role of the osteocyte in muscle atrophy in cancer patients, sarcopenia, spinal cord injury, Duchenne's muscular dystrophy, and other conditions associated with muscle deterioration.
RECENT FINDINGS: One type of bone cell, the osteocyte, appears to play a major role in muscle and bone crosstalk, whether physiological or pathological. Osteocytes are cells living within the bone-mineralized matrix. These cells are connected to each other by means of dendrites to create an intricately connected network. The osteocyte network has been shown to respond to different types of stimuli such as mechanical unloading, immobilization, aging, and cancer by producing osteocytes-derived factors. It is now becoming clear that some of these factors including sclerostin, RANKL, TGF-β, and TNF-α have detrimental effects on skeletal muscle. Bone and muscle not only communicate mechanically but also biochemically. Osteocyte-derived factors appear to contribute to the pathogenesis of muscle disease and could be used as a cellular target for new therapeutic approaches.

Keywords:  Cachexia; DMD; Muscle atrophy; Osteocytes; Sarcopenia

DOI:  https://doi.org/10.1007/s11914-023-00788-5
Front Physiol. 2023 ;14 1143966

Distinct microRNA and protein profiles of extracellular vesicles secreted from myotubes from morbidly obese donors with type 2 diabetes in response to electrical pulse stimulation.

Vigdis Aas, Reidun Øvstebø, Berit Sletbakk Brusletto, Trude Aspelin, Anne-Marie Siebke Trøseid, Saba Qureshi, Desima Shitandi Otundo Eid, Ole Kristoffer Olstad, Tuula A Nyman, Kari Bente Foss Haug.

  Lifestyle disorders like obesity, type 2 diabetes (T2D), and cardiovascular diseases can be prevented and treated by regular physical activity. During exercise, skeletal muscles release signaling factors that communicate with other organs and mediate beneficial effects of exercise. These factors include myokines, metabolites, and extracellular vesicles (EVs). In the present study, we have examined how electrical pulse stimulation (EPS) of myotubes, a model of exercise, affects the cargo of released EVs. Chronic low frequency EPS was applied for 24 h to human myotubes isolated and differentiated from biopsy samples from six morbidly obese females with T2D, and EVs, both exosomes and microvesicles (MV), were isolated from cell media 24 h thereafter. Size and concentration of EV subtypes were characterized by nanoparticle tracking analysis, surface markers were examined by flow cytometry and Western blotting, and morphology was confirmed by transmission electron microscopy. Protein content was assessed by high-resolution proteomic analysis (LC-MS/MS), non-coding RNA was quantified by Affymetrix microarray, and selected microRNAs (miRs) validated by real time RT-qPCR. The size and concentration of exosomes and MV were unaffected by EPS. Of the 400 miRs identified in the EVs, EPS significantly changed the level of 15 exosome miRs, of which miR-1233-5p showed the highest fold change. The miR pattern of MV was unaffected by EPS. Totally, about 1000 proteins were identified in exosomes and 2000 in MV. EPS changed the content of 73 proteins in exosomes, 97 in MVs, and of these four were changed in both exosomes and MV (GANAB, HSPA9, CNDP2, and ATP5B). By matching the EPS-changed miRs and proteins in exosomes, 31 targets were identified, and among these several promising signaling factors. Of particular interest were CNDP2, an enzyme that generates the appetite regulatory metabolite Lac-Phe, and miR-4433b-3p, which targets CNDP2. Several of the regulated miRs, such as miR-92b-5p, miR-320b, and miR-1233-5p might also mediate interesting signaling functions. In conclusion, we have used a combined transcriptome-proteome approach to describe how EPS affected the cargo of EVs derived from myotubes from morbidly obese patients with T2D, and revealed several new factors, both miRs and proteins, that might act as exercise factors.

Keywords:  electrical pulse stimulation (EPS); extracellular vescicles; human myotubes; microRNA; morbid obesity; proteomic; transcriptomic; type 2 diabetes (T2D)

DOI:  https://doi.org/10.3389/fphys.2023.1143966
bioRxiv. 2023 Apr 06. pii: 2023.04.06.535919. [Epub ahead of print]

Resistance Training Diminishes Mitochondrial Adaptations to Subsequent Endurance Training.

Paulo H C Mesquita, Joshua S Godwin, Bradley A Ruple, Casey L Sexton, Mason C McIntosh, Breanna J Mueller, Shelby C Osburn, C Brooks Mobley, Cleiton A Libardi, Kaelin C Young, L Bruce Gladden, Michael D Roberts, Andreas N Kavazis.

We investigated the effects of performing a period of resistance training (RT) on the performance and molecular adaptations to a subsequent period of endurance training (ET). Twenty-five young adults were divided into RT+ET (n=13), which underwent seven weeks of RT followed by seven weeks of ET, and ET-only (n=12), which performed seven weeks of ET. Body composition, endurance performance, and muscle biopsies were collected before RT (T1, baseline for RT+ET), before ET (T2, post RT for RT+ET and baseline for ET), and after ET (T3). Immunohistochemistry was performed to determine fiber cross-sectional area (fCSA), myonuclear content, myonuclear domain size, satellite cell number, and mitochondrial content. Western blots were used to quantify markers of mitochondrial remodeling. Citrate synthase activity and markers of ribosome content were also investigated. Resistance training improved body composition and strength, increased vastus lateralis thickness, mixed and type II fCSA, myonuclear number, markers of ribosome content, and satellite cell content (p<0.050). In response to ET, both groups similarly decreased body fat percentage and improved endurance performance (e.g., VO 2 max, and speed at which the onset of blood lactate accumulation occurred during the VO 2 max test). Levels of mitochondrial complexes I-IV in the ET-only group increased 32-66%, while the RT+ET group increased 1-11%. Additionally, mixed fiber relative mitochondrial content increased 15% in the ET-only group but decreased 13% in the RT+ET group. In conclusion, RT performed prior to ET had no additional benefits to ET adaptations. Moreover, prior RT seemed to impair mitochondrial adaptations to ET.
KEY POINTS SUMMARY: Resistance training is largely underappreciated as a method to improve endurance performance, despite reports showing it may improve mitochondrial function.Although several concurrent training studies are available, in this study we investigated the effects of performing a period resistance training on the performance and molecular adaptations to subsequent endurance training.Prior resistance training did not improve endurance performance and impaired most mitochondrial adaptations to subsequent endurance training, but that seemed to be a result of detraining from resistance training.

DOI: https://doi.org/10.1101/2023.04.06.535919
Mol Cell Biochem. 2023 Apr 20.

MYH7 in cardiomyopathy and skeletal muscle myopathy.

Yuan Gao, Lu Peng, Cuifen Zhao.

  Myosin heavy chain gene 7 (MYH7), a sarcomeric gene encoding the myosin heavy chain (myosin-7), has attracted considerable interest as a result of its fundamental functions in cardiac and skeletal muscle contraction and numerous nucleotide variations of MYH7 are closely related to cardiomyopathy and skeletal muscle myopathy. These disorders display significantly inter- and intra-familial variability, sometimes developing complex phenotypes, including both cardiomyopathy and skeletal myopathy. Here, we review the current understanding on MYH7 with the aim to better clarify how mutations in MYH7 affect the structure and physiologic function of sarcomere, thus resulting in cardiomyopathy and skeletal muscle myopathy. Importantly, the latest advances on diagnosis, research models in vivo and in vitro and therapy for precise clinical application have made great progress and have epoch-making significance. All the great advance is discussed here.

Keywords:  Cardiomyopathy; Genetic variant; Hypertrophic cardiomyopathy; MYH7; Myosin myopathy

DOI:  https://doi.org/10.1007/s11010-023-04735-x
Steroids. 2023 Apr 13. pii: S0039-128X(23)00068-5. [Epub ahead of print] 109240

Effects of exercise training on glucocorticoid-induced muscle atrophy: literature review.

Anderson G Macedo, Tiago A F Almeida, Danilo A Massini, Vinícius F De Paula, David M De Oliveira, Dalton M Pessôa Filho.

  Glucocorticoids (GCs) administration, such as cortisol acetate (CA) and dexamethasone (DEXA), is used worldwide due to their anti-inflammatory, anti-allergic, and immunosuppressive properties. However, muscle atrophy is one of the primary deleterious induced responses from the chronic treatment with GCs since it stimulates muscle degradation inhibiting muscle protein synthesis. Animal models allow a better understanding of the molecular pathways involved in this process of gene modulation and production of hypertrophic and atrophic proteins. The treatment with GCs, such as DEXA, promotes the reduction of hypertrophic proteins such as serine/threonine tyrosine kinase (AKT), protein kinase mammalian target of rapamycin (mTOR), and ribosomal protein S6 kinase (p70S6K) and increased gene expression or production of atrophic proteins, such as myostatin, muscle atrophic F-box (atrogin-1), or muscle ring finger protein-1 (MuRF-1). In both continuous exercise (CE) and resistance exercise (RE) forms, exercise training is used to mitigate muscle atrophy induced by GCs. The CE attenuated muscle atrophy induced by CA or DEXA in the plantaris and extensor digitorum longus muscle, while RE mitigated the DEXA-induced atrophy in plantaris and flexor hallux longus muscles. The RE response appears to have occurred by modulation of hypertrophic proteins through increased protein production or phosphorylated/total ratio of mTOR and p70S6K and decreased atrophic protein production of atrogin-1 and MuRF-1. CE needs future research to understand the molecular pathways of its protective response. Abreviations: GCs, glucocorticoids; CA, cortisol acetate. DEXA, dexamethason; ET, exercise training; CE, continuous exercise; RE, resistance exercise; AKT, serine/threonine tyrosine kinase; mTOR, protein kinase mammalian target of rapamycin; p70S6K, ribosomal protein S6 kinase; FOXO3A, forkead box 3A; atrogin-1, muscle atrophic F-box; MuRF-1, muscle ring finger protein; PI3K, phosphatidylinositol 3 kinase; IGF-I, Insulin-like Growth Factor-I; IRS-1, insulin receptor substrate; REDD1, regulated in development and DNA damage responses 1; HSP70, heat shock protein 70; GR, glucocorticoid receptor; Smad2, Cytoplasmic Smad2; Smad3, Cytoplasmic Smad3; CS, Cushing's syndrome.

Keywords:  dexamethasone; skeletal muscle; strength training

DOI:  https://doi.org/10.1016/j.steroids.2023.109240
Cell Metab. 2023 Apr 11. pii: S1550-4131(23)00094-3. [Epub ahead of print]

Pyruvate-supported flux through medium-chain ketothiolase promotes mitochondrial lipid tolerance in cardiac and skeletal muscles.

Timothy R Koves, Guo-Fang Zhang, Michael T Davidson, Alec B Chaves, Scott B Crown, Jordan M Johnson, Dorothy H Slentz, Paul A Grimsrud, Deborah M Muoio.

  Even-chain acylcarnitine (AC) metabolites, most of which are generated as byproducts of incomplete fatty acid oxidation (FAO), are viewed as biomarkers of mitochondrial lipid stress attributable to one or more metabolic bottlenecks in the β-oxidation pathway. The origins and functional implications of FAO bottlenecks remain poorly understood. Here, we combined a sophisticated mitochondrial phenotyping platform with state-of-the-art molecular profiling tools and multiple two-state mouse models of respiratory function to uncover a mechanism that connects AC accumulation to lipid intolerance, metabolic inflexibility, and respiratory inefficiency in skeletal muscle mitochondria. These studies also identified a short-chain carbon circuit at the C4 node of FAO wherein reverse flux of glucose-derived acetyl CoA through medium-chain ketothiolase enhances lipid tolerance and redox stability in heart mitochondria by regenerating free CoA and NAD+. The findings help to explain why diminished FAO capacity, AC accumulation, and metabolic inflexibility are tightly linked to poor health outcomes.

Keywords:  acylcarnitines; bioenergetics; exercise; fatty acid oxidation; heart; ketothiolase; metabolic flexibility; mitochondria; pyruvate; skeletal muscle

DOI:  https://doi.org/10.1016/j.cmet.2023.03.016
Aging Cell. 2023 Apr 20. e13849

Deletion of quinolinate phosphoribosyltransferase gene accelerates frailty phenotypes and neuromuscular decline with aging in a sex-specific pattern.

Tae Chung, Taylor Bopp, Chris Ward, Francesca M Notarangelo, Robert Schwarcz, Reyhan Westbrook, Qian-Li Xue, Jeremy Walston, Ahmet Hoke.

  Decline in neuromuscular function with aging is known to be a major determinant of disability and all-cause mortality in late life. Despite the importance of the problem, the neurobiology of age-associated muscle weakness is poorly understood. In a previous report, we performed untargeted metabolomics on frail older adults and discovered prominent alteration in the kynurenine pathway, the major route of dietary tryptophan degradation that produces neurotoxic intermediate metabolites. We also showed that neurotoxic kynurenine pathway metabolites are correlated with increased frailty score. For the present study, we sought to further examine the neurobiology of these neurotoxic intermediates by utilizing a mouse model that has a deletion of the quinolinate phosphoribosyltransferase (QPRT) gene, a rate-limiting step of the kynurenine pathway. QPRT-/- mice have elevated neurotoxic quinolinic acid level in the nervous system throughout their lifespan. We found that QPRT-/- mice have accelerated declines in neuromuscular function in an age- and sex-specific manner compared to control strains. In addition, the QPRT-/- mice show premature signs of frailty and body composition changes that are typical for metabolic syndrome. Our findings suggest that the kynurenine pathway may play an important role in frailty and age-associated muscle weakness.

Keywords:  age-associated muscle weakness; aging; frailty; kynurenine; neurodegeneration; neuromuscular junction; quinolinic acid; sarcopenia

DOI:  https://doi.org/10.1111/acel.13849
Sci Rep. 2023 Apr 21. 13(1): 6555

Degeneration of muscle spindles in a murine model of Pompe disease.

Bridgette Watkins, Jürgen Schultheiß, Andi Rafuna, Stefan Hintze, Peter Meinke, Benedikt Schoser, Stephan Kröger.

Pompe disease is a debilitating medical condition caused by a functional deficiency of lysosomal acid alpha-glucosidase (GAA). In addition to muscle weakness, people living with Pompe disease experience motor coordination deficits including an instable gait and posture. We reasoned that an impaired muscle spindle function might contribute to these deficiencies and therefore analyzed proprioception as well as muscle spindle structure and function in 4- and 8-month-old Gaa-/- mice. Gait analyses showed a reduced inter-limb and inter-paw coordination in Gaa-/- mice. Electrophysiological analyses of single-unit muscle spindle proprioceptive afferents revealed an impaired sensitivity of the dynamic and static component of the stretch response. Finally, a progressive degeneration of the sensory neuron and of the intrafusal fibers was detectable in Gaa-/- mice. We observed an increased abundance and size of lysosomes, a fragmentation of the inner and outer connective tissue capsule and a buildup of autophagic vacuoles in muscle spindles from 8-month-old Gaa-/- mice, indicating lysosomal defects and an impaired autophagocytosis. These results demonstrate a structural and functional degeneration of muscle spindles and an altered motor coordination in Gaa-/- mice. Similar changes could contribute to the impaired motor coordination in patients living with Pompe disease.

DOI: https://doi.org/10.1038/s41598-023-33543-y
Sci Rep. 2023 Apr 17. 13(1): 6240

Improvement of muscle strength in specific muscular regions in nusinersen-treated adult patients with 5q-spinal muscular atrophy.

Olivia Schreiber-Katz, Hannah Alexandra Siegler, Gary Wieselmann, Mareike Kumpe, Gresa Ranxha, Susanne Petri, Alma Osmanovic.

Real-world data have shown mild improvement of overall motor function in adult patients treated with nusinersen, the first approved therapy for 5q-spinal muscular atrophy (SMA). However, knowledge about preferably targeted muscle functions is sparse. The aim of this study was to evaluate strength of distinct muscles and body regions in adult SMA patients in the early course of nusinersen therapy. 72 muscles of 15 patients were tested on the Medical Research Council (MRC) 0-10 scale (translated into MRC %) from nusinersen start to 14 months of treatment. The whole body muscular strength improved slightly or remained stable in 80% of SMA patients with a median improvement of + 2%. However, relevant increases of muscle strength of distinct regions were identified in the proximal upper limbs and shoulder girdle (median + 8%) and in muscle groups with a preserved function pre-treatment, even in more advanced diseased SMA patients. MRC grading was additionally performed in seven patients enrolled during ongoing treatment. Here, further improvement of muscle strength until month 18-26 was seen with the highest increases in the proximal upper and lower limbs. Our findings suggest that sole evaluation of the overall muscle strength might underestimate nusinersen therapy benefits.

DOI: https://doi.org/10.1038/s41598-023-31617-5
Aging (Albany NY). 2023 Apr 19. 15

Single-cell transcriptomic analysis uncovers diverse and dynamic senescent cell populations.

Noah Wechter, Martina Rossi, Carlos Anerillas, Dimitrios Tsitsipatis, Yulan Piao, Jinshui Fan, Jennifer L Martindale, Supriyo De, Krystyna Mazan-Mamczarz, Myriam Gorospe.

  Senescence is a state of enduring growth arrest triggered by sublethal cell damage. Given that senescent cells actively secrete proinflammatory and matrix-remodeling proteins, their accumulation in tissues of older persons has been linked to many diseases of aging. Despite intense interest in identifying robust markers of senescence, the highly heterogeneous and dynamic nature of the senescent phenotype has made this task difficult. Here, we set out to comprehensively analyze the senescent transcriptome of human diploid fibroblasts at the individual-cell scale by performing single-cell RNA-sequencing analysis through two approaches. First, we characterized the different cell states in cultures undergoing senescence triggered by different stresses, and found distinct cell subpopulations that expressed mRNAs encoding proteins with roles in growth arrest, survival, and the secretory phenotype. Second, we characterized the dynamic changes in the transcriptomes of cells as they developed etoposide-induced senescence; by tracking cell transitions across this process, we found two different senescence programs that developed divergently, one in which cells expressed traditional senescence markers such as p16 (CDKN2A) mRNA, and another in which cells expressed long noncoding RNAs and splicing was dysregulated. Finally, we obtained evidence that the proliferation status at the time of senescence initiation affected the path of senescence, as determined based on the expressed RNAs. We propose that a deeper understanding of the transcriptomes during the progression of different senescent cell phenotypes will help develop more effective interventions directed at this detrimental cell population.

Keywords:  senescence; single-cell analysis; transcriptome

DOI:  https://doi.org/10.18632/aging.204666
Aging (Albany NY). 2023 Apr 20. 15

How can we modulate aging through nutrition and physical exercise? An epigenetic approach.

ALFA Score Consortium

  The World Health Organization predicts that by 2050, 2.1 billion people worldwide will be over 60 years old, a drastic increase from only 1 billion in 2019. Considering these numbers, strategies to ensure an extended "healthspan" or healthy longevity are urgently needed. The present study approaches the promotion of healthspan from an epigenetic perspective. Epigenetic phenomena are modifiable in response to an individual's environmental exposures, and therefore link an individual's environment to their gene expression pattern. Epigenetic studies demonstrate that aging is associated with decondensation of the chromatin, leading to an altered heterochromatin structure, which promotes the accumulation of errors. In this review, we describe how aging impacts epigenetics and how nutrition and physical exercise can positively impact the aging process, from an epigenetic point of view. Canonical histones are replaced by histone variants, concomitant with an increase in histone post-translational modifications. A slight increase in DNA methylation at promoters has been observed, which represses transcription of previously active genes, in parallel with global genome hypomethylation. Aging is also associated with deregulation of gene expression - usually provided by non-coding RNAs - leading to both the repression of previously transcribed genes and to the transcription of previously repressed genes. Age-associated epigenetic events are less common in individuals with a healthy lifestyle, including balanced nutrition, caloric restriction and physical exercise. Healthy aging is associated with more tightly condensed chromatin, fewer PTMs and greater regulation by ncRNAs.

Keywords:  aging; caloric restriction; epigenetics; nutrition; physical exercise

DOI:  https://doi.org/10.18632/aging.204668