bims-mitrat 2024-09-22 papers

bims-mitrat

Biomed News

on Mitochondrial Transplantation and Transfer

Issue of 2024‒09‒22
ten papers selected by
Gökhan Burçin Kubat, Gulhane Health Sciences Institute

Exercise training and changes in skeletal muscle mitochondrial proteins: from blots to "omics".
Intercellular nanotube-mediated mitochondrial transfer enhances T cell metabolic fitness and antitumor efficacy.
Surface engineering enhances the therapeutic potential of systemically delivered extracellular vesicles following acute myocardial infarction.
Cell transplantation-mediated dystrophin supplementation efficacy in Duchenne muscular dystrophy mouse motor function improvement demonstrated by enhanced skeletal muscle fatigue tolerance.
Resistance training suppresses accumulation of senescent fibro-adipogenic progenitors and senescence-associated secretory phenotype in aging rat skeletal muscle.
Exercise Alleviates Cardiovascular Diseases by Improving Mitochondrial Homeostasis.
Subcutaneous adipose tissue and skeletal muscle mitochondria following weight loss.
The androgen receptor in mesenchymal progenitors regulates skeletal muscle mass via Igf1 expression in male mice.
Relative muscle indices and healthy reference values for sarcopenia assessment using T10 through L5 computed tomography skeletal muscle area.
Sarcopenia.

Crit Rev Biochem Mol Biol. 2024 Sep 17. 1-23

Exercise training and changes in skeletal muscle mitochondrial proteins: from blots to "omics".

Elizabeth G Reisman, Nikeisha J Caruana, David J Bishop.

  Mitochondria are essential, membrane-enclosed organelles that consist of ∼1100 different proteins, which allow for many diverse functions critical to maintaining metabolism. Highly metabolic tissues, such as skeletal muscle, have a high mitochondrial content that increases with exercise training. The classic western blot technique has revealed training-induced increases in the relatively small number of individual mitochondrial proteins studied (∼5% of the >1100 proteins in MitoCarta), with some of these changes dependent on the training stimulus. Proteomic approaches have identified hundreds of additional mitochondrial proteins that respond to exercise training. There is, however, surprisingly little crossover in the mitochondrial proteins identified in the published human training studies. This suggests that to better understand the link between training-induced changes in mitochondrial proteins and metabolism, future studies need to move beyond maximizing protein detection to adopting methods that will increase the reliability of the changes in protein abundance observed.

Keywords:  Mitochondria; fiber type; proteins; proteomics; skeletal muscle; training

DOI:  https://doi.org/10.1080/10409238.2024.2383408
Cell. 2024 Sep 12. pii: S0092-8674(24)00956-5. [Epub ahead of print]

Intercellular nanotube-mediated mitochondrial transfer enhances T cell metabolic fitness and antitumor efficacy.

Jeremy G Baldwin, Christoph Heuser-Loy, Tanmoy Saha, Roland C Schelker, Dragana Slavkovic-Lukic, Nicholas Strieder, Inmaculada Hernandez-Lopez, Nisha Rana, Markus Barden, Fabio Mastrogiovanni, Azucena Martín-Santos, Andrea Raimondi, Philip Brohawn, Brandon W Higgs, Claudia Gebhard, Veena Kapoor, William G Telford, Sanjivan Gautam, Maria Xydia, Philipp Beckhove, Sina Frischholz, Kilian Schober, Zacharias Kontarakis, Jacob E Corn, Matteo Iannacone, Donato Inverso, Michael Rehli, Jessica Fioravanti, Shiladitya Sengupta, Luca Gattinoni.

  Mitochondrial loss and dysfunction drive T cell exhaustion, representing major barriers to successful T cell-based immunotherapies. Here, we describe an innovative platform to supply exogenous mitochondria to T cells, overcoming these limitations. We found that bone marrow stromal cells establish nanotubular connections with T cells and leverage these intercellular highways to transplant stromal cell mitochondria into CD8+ T cells. Optimal mitochondrial transfer required Talin 2 on both donor and recipient cells. CD8+ T cells with donated mitochondria displayed enhanced mitochondrial respiration and spare respiratory capacity. When transferred into tumor-bearing hosts, these supercharged T cells expanded more robustly, infiltrated the tumor more efficiently, and exhibited fewer signs of exhaustion compared with T cells that did not take up mitochondria. As a result, mitochondria-boosted CD8+ T cells mediated superior antitumor responses, prolonging animal survival. These findings establish intercellular mitochondrial transfer as a prototype of organelle medicine, opening avenues to next-generation cell therapies.

Keywords:  CAR T therapy; CD8(+) T cells; TCR-T therapy; TIL therapy; Talin 2; bone marrow stromal cells; cancer immunotherapy; immune metabolism; mitochondrial transfer; nanotubes

DOI:  https://doi.org/10.1016/j.cell.2024.08.029
FASEB J. 2024 Sep 30. 38(18): e70070

Surface engineering enhances the therapeutic potential of systemically delivered extracellular vesicles following acute myocardial infarction.

Kyle I Mentkowski, Touba Tarvirdizadeh, Cody A Manzanero, Lisa A Eagler, Jennifer K Lang.

  The objective of the study was to assess the therapeutic efficacy of targeting remote zone cardiomyocytes with cardiosphere-derived cell (CDC) extracellular vesicles (EVs) delivered via intramyocardial and intravenous routes following acute myocardial infarction (MI). Cardiomyocyte (CM) cell death plays a significant role in left ventricular (LV) remodeling and cardiac dysfunction following MI. While EVs secreted by CDCs have shown efficacy in promoting cardiac repair in preclinical models of MI, their translational potential is limited by their biodistribution and requirement for intramyocardial delivery. We hypothesized that engineering the surface of EVs to target cardiomyocytes would enhance their therapeutic efficacy following systemic delivery in a model of acute MI. CDC-derived EVs were engineered to express a CM-specific binding peptide (CMP) on their surface and characterized for size, morphology, and protein expression. Mice with acute MI underwent both intramyocardial and intravenous delivery of EVs, CMP-EVs and placebo in a double-blind study. LVEF was assessed by echo at 2- and 28-days post-MI and tissue samples processed for assessment of EV biodistribution and histological endpoints. CMP-EVs demonstrated superior cardiac targeting and retention when compared with unmodified EVs 24 h post-MI. Mice treated with IV delivered CMP-EVs demonstrated a significant improvement in LVEF and a significant reduction in remote zone cardiomyocyte apoptosis when compared with IV delivered non-targeted EVs at 28-day post-MI. Systemic administration of CMP-EVs improved cardiac function and reduced remote zone cardiomyocyte apoptosis compared with IV-administered unmodified EVs, demonstrating a strategy to optimize therapeutic EV delivery post-MI.

Keywords:  cardiomyocyte apoptosis; cardiosphere‐derived cells; extracellular vesicles; intravenous administration; myocardial infarction; nanoparticle engineering; targeted delivery

DOI:  https://doi.org/10.1096/fj.202400828R
Stem Cell Res Ther. 2024 Sep 19. 15(1): 313

Cell transplantation-mediated dystrophin supplementation efficacy in Duchenne muscular dystrophy mouse motor function improvement demonstrated by enhanced skeletal muscle fatigue tolerance.

Clémence Kiho Bourgeois Yoshioka, Nana Takenaka-Ninagawa, Megumi Goto, Mayuho Miki, Daiki Watanabe, Masamichi Yamamoto, Tomoki Aoyama, Hidetoshi Sakurai.

  BACKGROUND: Duchenne muscular dystrophy (DMD) is an incurable neuromuscular disease leading to progressive skeletal muscle weakness and fatigue. Cell transplantation in murine models has shown promise in supplementing the lack of the dystrophin protein in DMD muscles. However, the establishment of novel, long-term, relevant methods is needed to assess its efficiency on the DMD motor function. By applying newly developed methods, this study aimed to evaluate the functional and molecular effects of cell therapy-mediated dystrophin supplementation on DMD muscles.METHODS: Dystrophin was supplemented in the gastrocnemius of a 5-week-old immunodeficient DMD mouse model (Dmd-null/NSG) by intramuscular xenotransplantation of healthy human immortalized myoblasts (Hu5/KD3). A long-term time-course comparative study was conducted between wild-type, untreated DMD, and dystrophin supplemented-DMD mouse muscle functions and histology. A novel GO-ATeam2 transgenic DMD mouse model was also generated to assess in vivo real-time ATP levels in gastrocnemius muscles during repeated contractions.
RESULTS: We found that 10.6% dystrophin supplementation in DMD muscles was sufficient to prevent low values of gastrocnemius maximal isometric contraction torque (MCT) at rest, while muscle fatigue tolerance, assessed by MCT decline after treadmill running, was fully ameliorated in 21-week-old transplanted mice. None of the dystrophin-supplemented fibers were positive for muscle damage markers after treadmill running, with 85.4% demonstrating the utilization of oxidative metabolism. Furthermore, ATP levels in response to repeated muscle contractions tended to improve, and mitochondrial activity was significantly enhanced in dystrophin supplemented-fibers.
CONCLUSIONS: Cell therapy-mediated dystrophin supplementation efficiently improved DMD muscle functions, as evaluated using newly developed evaluation methods. The enhanced muscle fatigue tolerance in 21-week-old mice was associated with the preferential regeneration of damage-resistant and oxidative fibers, highlighting increased mitochondrial activity, after cell transplantation. These findings significantly contribute to a more in-depth understanding of DMD pathogenesis.

Keywords:  Cell transplantation; Duchenne muscular dystrophy mouse model; Dystrophin supplementation; GO-ATeam2 transgenic mouse model; In vivo ATP imaging; Mitochondrial activity; Motor function evaluation; Muscle fatigue tolerance; Oxidative slow fibers

DOI:  https://doi.org/10.1186/s13287-024-03922-x
Geroscience. 2024 Sep 19.

Resistance training suppresses accumulation of senescent fibro-adipogenic progenitors and senescence-associated secretory phenotype in aging rat skeletal muscle.

Yung-Li Hung, Ayami Sato, Yuka Takino, Akihito Ishigami, Shuichi Machida.

  Accumulation of senescent cells in tissues contributes to multiple aging-related pathologies. Senescent fibro-adipogenic progenitors (FAPs) contribute to aging-related muscle atrophy. Resistance training can help to maintain skeletal muscle mass, improve mobility, and reduce certain health risks commonly associated with aging. We investigated, using rat model, the impact of resistance training on FAPs in aging skeletal muscle, which remains unclear. Twenty-two-month-old female rats were divided into sedentary and training groups. The training group rodents were trained to climb a ladder while bearing a load for 20 training sessions over 2 months, after which, the flexor hallucis longus muscles were collected and analyzed. Senescent cells were identified using a senescence-associated β-galactosidase stain and p21 immunohistochemistry (IHC), and FAPs were identified using platelet-derived growth factor receptor alpha IHC. The results indicate that resistance training in rats prevented aging-associated skeletal muscle atrophy and suppressed M2 polarization of macrophages. The number of senescent cells was significantly reduced in the 24-month-old training group, with most of them being FAPs. Conversely, the number of senescent FAPs increased significantly in the 24-month-old sedentary group compared with that in the 18-month-old sedentary group. The number of senescent FAPs in the 24-month-old training group decreased significantly. Resistance training also suppressed the senescence-associated secretory phenotype (SASP). The killer T cell-specific marker, CD8α, was elevated in the skeletal muscles of the aging rats following resistance training, indicating upregulation of recognition and elimination of senescent cells. Overall, resistance training suppressed the accumulation of senescent FAPs and acquisition of SASP in aging skeletal muscles.

Keywords:  Fibro-adipogenic progenitors; Resistance training; Sarcopenia; Senescent cells

DOI:  https://doi.org/10.1007/s11357-024-01338-2
J Am Heart Assoc. 2024 Sep 18. e036555

Exercise Alleviates Cardiovascular Diseases by Improving Mitochondrial Homeostasis.

Huijie Zhang, Yuxuan Zhang, Jiaqiao Zhang, Dandan Jia.

  Engaging in regular exercise and physical activity contributes to delaying the onset of cardiovascular diseases (CVDs). However, the physiological mechanisms underlying the benefits of regular exercise or physical activity in CVDs remain unclear. The disruption of mitochondrial homeostasis is implicated in the pathological process of CVDs. Exercise training effectively delays the onset and progression of CVDs by significantly ameliorating the disruption of mitochondrial homeostasis. This includes improving mitochondrial biogenesis, increasing mitochondrial fusion, decreasing mitochondrial fission, promoting mitophagy, and mitigating mitochondrial morphology and function. This review provides a comprehensive overview of the benefits of physical exercise in the context of CVDs, establishing a connection between the disruption of mitochondrial homeostasis and the onset of these conditions. Through a detailed examination of the underlying molecular mechanisms within mitochondria, the study illuminates how exercise can provide innovative perspectives for future therapies for CVDs.

Keywords:  cardiovascular diseases; exercise; exerkines; mitochondrial homeostasis

DOI:  https://doi.org/10.1161/JAHA.124.036555
Trends Endocrinol Metab. 2024 Sep 16. pii: S1043-2760(24)00221-2. [Epub ahead of print]

Subcutaneous adipose tissue and skeletal muscle mitochondria following weight loss.

Birgitta W van der Kolk, Eija Pirinen, Rachel Nicoll, Kirsi H Pietiläinen, Sini Heinonen.

  Obesity is a major global health issue with various metabolic complications. Both bariatric surgery and dieting achieve weight loss and improve whole-body metabolism, but vary in their ability to maintain these improvements over time. Adipose tissue and skeletal muscle metabolism are crucial in weight regulation, and obesity is linked to mitochondrial dysfunction in both tissues. The impact of bariatric surgery versus dieting on adipose tissue and skeletal muscle mitochondrial metabolism remains to be elucidated. Understanding the molecular pathways that modulate tissue metabolism following weight loss holds potential for identifying novel therapeutic targets in obesity management. This narrative review summarizes current knowledge on mitochondrial metabolism following bariatric surgery and diet-induced weight loss in adipose tissue and skeletal muscle, and sheds light on their respective effects.

Keywords:  adipose tissue; bariatric surgery; caloric restriction; mitochondria; obesity; skeletal muscle

DOI:  https://doi.org/10.1016/j.tem.2024.08.002
Proc Natl Acad Sci U S A. 2024 Sep 24. 121(39): e2407768121

The androgen receptor in mesenchymal progenitors regulates skeletal muscle mass via Igf1 expression in male mice.

Hiroshi Sakai, Hideaki Uno, Harumi Yamakawa, Kaori Tanaka, Aoi Ikedo, Akiyoshi Uezumi, Yasuyuki Ohkawa, Yuuki Imai.

  Androgens exert their effects primarily by binding to the androgen receptor (AR), a ligand-dependent nuclear receptor. While androgens have anabolic effects on skeletal muscle, previous studies reported that AR functions in myofibers to regulate skeletal muscle quality, rather than skeletal muscle mass. Therefore, the anabolic effects of androgens are exerted via nonmyofiber cells. In this context, the cellular and molecular mechanisms of AR in mesenchymal progenitors, which play a crucial role in maintaining skeletal muscle homeostasis, remain largely unknown. In this study, we demonstrated expression of AR in mesenchymal progenitors and found that targeted AR ablation in mesenchymal progenitors reduced limb muscle mass in mature adult, but not young or aged, male mice, although fatty infiltration of muscle was not affected. The absence of AR in mesenchymal progenitors led to remarkable perineal muscle hypotrophy, regardless of age, due to abnormal regulation of transcripts associated with cell death and extracellular matrix organization. Additionally, we revealed that AR in mesenchymal progenitors regulates the expression of insulin-like growth factor 1 (Igf1) and that IGF1 administration prevents perineal muscle atrophy in a paracrine manner. These findings indicate that the anabolic effects of androgens regulate skeletal muscle mass via, at least in part, AR signaling in mesenchymal progenitors.

Keywords:  Igf1; androgen receptor; mesenchymal progenitors; skeletal muscle

DOI:  https://doi.org/10.1073/pnas.2407768121
Sci Rep. 2024 09 18. 14(1): 21799

Relative muscle indices and healthy reference values for sarcopenia assessment using T10 through L5 computed tomography skeletal muscle area.

Brian A Derstine, Sven A Holcombe, Nicholas C Wang, Brian E Ross, June A Sullivan, Stewart C Wang, Grace L Su.

  Sarcopenia is the age-related loss of skeletal muscle mass and function. Computed tomography (CT) assessments of sarcopenia utilize measurements of skeletal muscle cross-sectional area (SMA), radiation attenuation (SMRA), and intramuscular adipose tissue (IMAT). Unadjusted SMA is strongly correlated with both height and body mass index (BMI); therefore, SMA must be adjusted for body size to assess sarcopenic low muscle mass fairly in individuals of different heights and BMI. SMA/height (rather than SMA/height2 ) provides optimal height adjustment, and vertebra-specific relative muscle index (RMI) equations optimally adjust for both height and BMI. Since L3 measurement is not available in all CT scans, sarcopenic low muscle mass may be assessed using other levels. Both a mid-vertebral slice and an inferior slice have been used to define 'L3 SMA', but the effect of vertebral slice location on SMA measurements is unexplored. Healthy reference values for skeletal muscle measures at mid- and inferior vertebra slices between T10 and L5, have not yet been reported. We extracted T10 through L5 SMA, SMRA, and IMAT at a mid-vertebral and inferior slice using non-contrast-enhanced CT scans from healthy, adult kidney donor candidates between age 18 and 73. We compared paired differences in SMA between the mid-vertebral slice versus the inferior slice. We calculated the skeletal muscle gauge as SMGHT=SMRA∗SMIHT . We used allometric analysis to find the optimal height scaling power for SMA. To enable comparisons with other published reference cohorts, we computed two height-adjusted measures; SMIHT=SMA/height (optimal) and SMIHT2=SMA/height2 (traditional). Using the young, healthy reference cohort, we utilized multiple linear regression to calculate relative muscle index z-scores ( RMIHT , RMIHT2 ), which adjust for both height and BMI, at each vertebra level. We assessed Pearson correlations of each muscle area measure versus age, height, weight, and BMI separately by sex and vertebra number. We assessed the differences in means between age 18-40 versus 20-40 as the healthy, young adult reference group. We reported means, standard deviations, and sarcopenia cutpoints (mean-2SD and 5th percentile) by sex and age group for all measures. Sex-specific allometric analysis showed that height to the power of one was the optimal adjustment for SMA in both men and women at all vertebra levels. Differences between mid-vertebra and inferior slice SMA were statistically significant at each vertebra level, except for T10 in men. SMIHT was uncorrelated with height, whereas SMIHT2 was negatively correlated with height at all vertebra levels. Both SMIHT and SMIHT2 were positively correlated with BMI at all vertebra levels. RMIHT was uncorrelated with BMI, weight, and height (minimal positive correlation in women at L3inf , L4mid , and L5inf ) whereas RMIHT2 was uncorrelated with BMI, but negatively correlated with height and weight at all levels. There were no significant differences in SMA between 18-40 versus 20-40 age groups. Healthy reference values and sarcopenic cutpoints are reported stratified by sex, vertebra level, and age group for each measure. Height to the power of one (SMA/height) is the optimal height adjustment factor for SMA at all levels between T10mid through L5inf . The use of SMA/height2 should be discontinued as it retains a significant negative correlation with height and is therefore biased towards identifying sarcopenia in taller individuals. Measurement of SMA at a mid-vertebral slice is significantly different from measurement of SMA at an inferior aspect slice. Reference values should be used for the appropriate slice. We report sarcopenic healthy reference values for skeletal muscle measures at the mid-vertebral and inferior aspect slice for T10 through L5 vertebra levels. Relative muscle index (RMI) equations developed here minimize correlation with both height and BMI, producing unbiased assessments of relative muscle mass across the full range of body sizes. We recommend the use of these RMI equations in other cohorts.

Keywords:  Morphomics; Sarcopenia; Skeletal muscle

DOI:  https://doi.org/10.1038/s41598-024-71613-x
Nat Rev Dis Primers. 2024 Sep 19. 10(1): 68

Sarcopenia.

Avan A Sayer, Rachel Cooper, Hidenori Arai, Peggy M Cawthon, Marie-Josiane Ntsama Essomba, Roger A Fielding, Miranda D Grounds, Miles D Witham, Alfonso J Cruz-Jentoft.

Sarcopenia is the accelerated loss of skeletal muscle mass and function commonly, but not exclusively, associated with advancing age. It is observed across many species including humans in whom it can lead to decline in physical function and mobility as well as to increased risk of adverse outcomes including falls, fractures and premature mortality. Although prevalence estimates vary because sarcopenia has been defined in different ways, even using a conservative approach, the prevalence is between 5% and 10% in the general population. A life course framework has been proposed for understanding not only the occurrence of sarcopenia in later life but also influences operating at earlier life stages with potentially important implications for preventive strategies. Harnessing progress in understanding the hallmarks of ageing has been key to understanding sarcopenia pathophysiology. Considerable convergence in approaches to diagnosis of sarcopenia has occurred over the last 10 years, with a growing emphasis on the central importance of muscle strength. Resistance exercise is currently the mainstay of treatment; however, it is not suitable for all. Hence, adjunctive and alternative treatments to improve quality of life are needed. An internationally agreed approach to definition and diagnosis will enable a step change in the field and is likely to be available in the near future through the Global Leadership Initiative in Sarcopenia.

DOI: https://doi.org/10.1038/s41572-024-00550-w