bims-moremu 2023-09-03 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2023–09–03
nineteen papers selected by
Anna Vainshtein, Craft Science Inc.

Impaired age-associated mitochondrial translation is mitigated by exercise and PGC-1α.
Genomics and Biology of Exercise, Where Are We Now?
Ageing of skeletal muscle extracellular matrix and mitochondria: finding a potential link.
Nanoparticles systemically biodistribute to regenerating skeletal muscle in DMD.
VMHdm/cSF-1 neuronal circuits regulate skeletal muscle PGC1-α via the sympathoadrenal drive.
Network of muscle fibers activation facilitates inter-muscular coordination, adapts to fatigue and reflects muscle function.
The Resistance Training Effects on Skeletal Muscle Stem Cells in Older Adult: A Systematic Review and Meta-Analysis.
Skeletal muscle function is altered in male mice on low dose androgen receptor antagonist or estrogen receptor agonist.
Transcriptional Profiling of Skeletal Muscle Stem Cells After In Vivo Engraftment into a Heterologous Niche Environment.
Resistance Exercise Training Rescues Mitochondrial Dysfunction in Skeletal Muscle of Patients with Myotonic Dystrophy Type 1.
Disease modeling and gene correction of LGMDR21 iPSCs elucidates the role of POGLUT1 in skeletal muscle maintenance, regeneration, and the satellite cell niche.
Optogenetic Calcium Ion Influx in Myoblasts and Myotubes by Near-Infrared Light Using Upconversion Nanoparticles.
Long-term muscle-specific overexpression of DOK7 in mice using AAV9-tMCK-DOK7.
Farnesol prevents aging-related muscle weakness in mice through enhanced farnesylation of Parkin-interacting substrate.
The role of nutrition in the prevention of sarcopenia.
Does Exercise Influence Skeletal Muscle by Modulating Mitochondrial Functions via Regulating MicroRNAs? A Systematic Review.
Agent-based model demonstrates the impact of nonlinear, complex interactions between cytokines on muscle regeneration.
Comparative analysis of the myoglobin gene in whales and humans reveals evolutionary changes in regulatory elements and expression levels.
Myo-differentiation reporter screen reveals NF-Y as an activator of PAX3-FOXO1 in rhabdomyosarcoma.

Proc Natl Acad Sci U S A. 2023 Sep 05. 120(36): e2302360120

Impaired age-associated mitochondrial translation is mitigated by exercise and PGC-1α.

Laura M de Smalen, Anastasiya Börsch, Aurel B Leuchtmann, Jonathan F Gill, Danilo Ritz, Mihaela Zavolan, Christoph Handschin.

  Sarcopenia, the age-related loss of skeletal muscle mass and function, can dramatically impinge on quality of life and mortality. While mitochondrial dysfunction and imbalanced proteostasis are recognized as hallmarks of sarcopenia, the regulatory and functional link between these processes is underappreciated and unresolved. We therefore investigated how mitochondrial proteostasis, a crucial process that coordinates the expression of nuclear- and mitochondrial-encoded mitochondrial proteins with supercomplex formation and respiratory activity, is affected in skeletal muscle aging. Intriguingly, a robust mitochondrial translation impairment was observed in sarcopenic muscle, which is regulated by the peroxisome proliferator-activated receptor γ coactivator 1 α (PGC-1α) with the estrogen-related receptor α (ERRα). Exercise, a potent inducer of PGC-1α activity, rectifies age-related reduction in mitochondrial translation, in conjunction with quality control pathways. These results highlight the importance of mitochondrial proteostasis in muscle aging, and elucidate regulatory interactions that underlie the powerful benefits of physical activity in this context.

Keywords:  aging; mitochondria; proteostasis; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.1073/pnas.2302360120
Clin J Sport Med. 2023 Sep 01. 33(5): e112-e114

Genomics and Biology of Exercise, Where Are We Now?

Danielle Hiam, Patrice Jones, Yannis Pitsiladis, Nir Eynon.

DOI: https://doi.org/10.1097/JSM.0000000000001012
Ann Med. 2023 ;55(2): 2240707

Ageing of skeletal muscle extracellular matrix and mitochondria: finding a potential link.

Lubing Cai, Luze Shi, Zhen Peng, Yaying Sun, Jiwu Chen.

  Aim: To discuss the progress of extracellular matrix (ECM) characteristics, mitochondrial homeostasis, and their potential crosstalk in the pathogenesis of sarcopenia, a geriatric syndrome characterized by a generalized and progressive reduction in muscle mass, strength, and physical performance.Methods: This review focuses on the anatomy and physiology of skeletal muscle, alterations of ECM and mitochondria during ageing, and the role of the interplay between ECM and mitochondria in the pathogenesis of sarcopenia.Results: Emerging evidence points to a clear interplay between mitochondria and ECM in various tissues and organs. Under the ageing process, the ECM undergoes changes in composition and physical properties that may mediate mitochondrial changes via the systematic metabolism, ROS, SPARC pathway, and AMPK/PGC-1α signalling, which in turn exacerbate muscle degeneration. However, the precise effects of such crosstalk on the pathobiology of ageing, particularly in skeletal muscle, have not yet been fully understood.Conclusion: The changes in skeletal muscle ECM and mitochondria are partially responsible for the worsened muscle function during the ageing process. A deeper understanding of their alterations and interactions in sarcopenic patients can help prevent sarcopenia and improve its prognoses.

Keywords:  Ageing; extracellular matrix; mitochondria; reactive oxygen species; sarcopenia

DOI:  https://doi.org/10.1080/07853890.2023.2240707
J Nanobiotechnology. 2023 Aug 29. 21(1): 303

Nanoparticles systemically biodistribute to regenerating skeletal muscle in DMD.

Michael R Hicks, Xiangsheng Liu, Courtney S Young, Kholoud Saleh, Ying Ji, Jinhong Jiang, Michael R Emami, Ekaterina Mokhonova, Melissa J Spencer, Huan Meng, April D Pyle.

Skeletal muscle disease severity can often progress asymmetrically across muscle groups and heterogeneously within tissues. An example is Duchenne Muscular Dystrophy (DMD) in which lack of dystrophin results in devastating skeletal muscle wasting in some muscles whereas others are spared or undergo hypertrophy. An efficient, non-invasive approach to identify sites of asymmetry and degenerative lesions could enable better patient monitoring and therapeutic targeting of disease. In this study, we utilized a versatile intravenously injectable mesoporous silica nanoparticle (MSNP) based nanocarrier system to explore mechanisms of biodistribution in skeletal muscle of mdx mouse models of DMD including wildtype, dystrophic, and severely dystrophic mice. Moreover, MSNPs could be imaged in live mice and whole muscle tissues enabling investigation of how biodistribution is altered by different types of muscle pathology such as inflammation or fibrosis. We found MSNPs were tenfold more likely to aggregate within select mdx muscles relative to wild type, such as gastrocnemius and quadriceps. This was accompanied by decreased biodistribution in off-target organs. We found the greatest factor affecting preferential delivery was the regenerative state of the dystrophic skeletal muscle with the highest MSNP abundance coinciding with the regions showing the highest level of embryonic myosin staining and intramuscular macrophage uptake. To demonstrate, muscle regeneration regulated MSNP distribution, we experimentally induced regeneration using barium chloride which resulted in a threefold increase of intravenously injected MSNPs to sites of regeneration 7 days after injury. These discoveries provide the first evidence that nanoparticles have selective biodistribution to skeletal muscle in DMD to areas of active regeneration and that nanoparticles could enable diagnostic and selective drug delivery in DMD skeletal muscle.

DOI: https://doi.org/10.1186/s12951-023-01994-0
Mol Metab. 2023 Aug 24. pii: S2212-8778(23)00126-6. [Epub ahead of print] 101792

VMHdm/cSF-1 neuronal circuits regulate skeletal muscle PGC1-α via the sympathoadrenal drive.

Takuya Yoshida, Mina Fujitani, Scotlynn Farmer, Ami Harada, Zhen Shi, Jenny J Lee, Arely Tinajero, Ashish K Singha, Teppei Fujikawa.

OBJECTIVE: To adapt to metabolically challenging environments, the central nervous system (CNS) orchestrates metabolism of peripheral organs including skeletal muscle. The organ-communication between the CNS and skeletal muscle has been investigated, yet our understanding of the neuronal pathway from the CNS to skeletal muscle is still limited. Neurons in the dorsomedial and central parts of the ventromedial hypothalamic nucleus (VMHdm/c) expressing steroidogenic factor-1 (VMHdm/cSF-1 neurons) are key for metabolic adaptations to exercise, including increased basal metabolic rate and skeletal muscle mass in mice. However, the mechanisms by which VMHdm/cSF-1 neurons regulate skeletal muscle function remain unclear. Here, we show that VMHdm/cSF-1 neurons increase the sympathoadrenal activity and regulate skeletal muscle peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) in mice via multiple downstream nodes.
METHODS: Optogenetics was used to specifically manipulate VMHdm/cSF-1 neurons combined with genetically-engineered mice and surgical manipulation of the sympathoadrenal activity.
RESULTS: Optogenetic activation of VMHdm/cSF-1 neurons dramatically elevates mRNA levels of skeletal muscle Pgc-1α, which regulates a spectrum of skeletal muscle function including protein synthesis and metabolism. Mechanistically, the sympathoadrenal drive coupled with β2 adrenergic receptor (β2AdR) is essential for VMHdm/cSF-1 neurons-mediated increases in skeletal muscle PGC1-α. Specifically, both adrenalectomy and β2AdR knockout block augmented skeletal muscle PGC1-α by VMHdm/cSF-1 neuronal activation. Optogenetic functional mapping reveals that downstream nodes of VMHdm/cSF-1 neurons are functionally redundant to increase circulating epinephrine and skeletal muscle PGC1-α.
CONCLUSIONS: Collectively, we propose that VMHdm/cSF-1 neurons-skeletal muscle pathway, VMHdm/cSF-1 neurons→multiple downstream nodes→the adrenal gland→skeletal muscle β2AdR, underlies augmented skeletal muscle function for metabolic adaptations.

DOI: https://doi.org/10.1016/j.molmet.2023.101792
Commun Biol. 2023 08 30. 6(1): 891

Network of muscle fibers activation facilitates inter-muscular coordination, adapts to fatigue and reflects muscle function.

Sergi Garcia-Retortillo, Carlos Romero-Gómez, Plamen Ch Ivanov.

Fundamental movement patterns require continuous skeletal muscle coordination, where muscle fibers with different timing of activation synchronize their dynamics across muscles with distinct functions. It is unknown how muscle fibers integrate as a network to generate and fine tune movements. We investigate how distinct muscle fiber types synchronize across arm and chest muscles, and respond to fatigue during maximal push-up exercise. We uncover that a complex inter-muscular network of muscle fiber cross-frequency interactions underlies push-up movements. The network exhibits hierarchical organization (sub-networks/modules) with specific links strength stratification profile, reflecting distinct functions of muscles involved in push-up movements. We find network reorganization with fatigue where network modules follow distinct phase-space trajectories reflecting their functional role and adaptation to fatigue. Consistent with earlier observations for squat movements under same protocol, our findings point to general principles of inter-muscular coordination for fundamental movements, and open a new area of research, Network Physiology of Exercise.

DOI: https://doi.org/10.1038/s42003-023-05204-3
Cell J. 2023 Aug 01. pii: 704814. [Epub ahead of print]25(8): 513-523

The Resistance Training Effects on Skeletal Muscle Stem Cells in Older Adult: A Systematic Review and Meta-Analysis.

Diaco Heidari, Hossein Shirvani, Behzad Bazgir, Alireza Shamsoddini.

  The objective of this systematic review and meta-analysis is to examine the effects of resistance exercise training on muscle stem cells in older adults. A database search was performed (PubMed, Scopus, Web of Science and Google Scholar) to identify controlled clinical trials in English language. The mean difference (MD) with 95% confidence intervals (CIs) and overall effect size were calculated for all comparisons. The PEDro scale was used to assess the methodological quality. Nineteen studies were included in the review. The meta-analysis found a significant effect of resistance training (RT) on muscle stem cells in the elderly (difference in means=-0.008, Z=-3.415, P=0.001). Also, muscle stem cells changes were similar in men and women (difference in means=-0.004, Z=-1.558, P=0.119) and significant changes occur in type II muscle fibers (difference in means=-0.017, Z=-7.048, P=0.000). Resistance-type exercise training significantly increased muscle stem cells content in intervention group that this result is similar in men and womenthis increase occurred more in type II muscle fibers.

Keywords:  Elderly; Muscle Stem Cells; Older Adult; Resistance Training; Satellite Cells

DOI:  https://doi.org/10.22074/cellj.2023.1986679.1206
Endocrinology. 2023 Aug 26. pii: bqad132. [Epub ahead of print]

Skeletal muscle function is altered in male mice on low dose androgen receptor antagonist or estrogen receptor agonist.

Brent A Momb, Gillian K Szabo, Joshua P Mogus, Stuart R Chipkin, Laura N Vandenberg, Mark S Miller.

  In males, skeletal muscle function may be altered by shifts in either circulating testosterone or estrogen. We examined the effect of acute (2 week) exposures to 17α-ethinyl estradiol (EE2), an estrogen receptor (ER) agonist, or flutamide, an androgen receptor (AR) antagonist, on the contractile function of individual skeletal muscle fibers from slow-contracting soleus and fast-contracting extensor digitorum longus muscles from adult male mice. Single fiber specific tension (force divided by cross-sectional area) was decreased with flutamide treatment in all myosin heavy chain fiber types examined (MHC I, IIA and IIB); similar effects were observed with EE2-treatment but only in the fastest-contracting MHC IIB fibers. The decreases in maximally Ca2+-activated specific tension were primarily a result of fewer strongly bound myosin-actin cross-bridges, with flutamide treatment also showing lower myofilament lattice stiffness. Myosin-actin cross-bridge kinetics were slower in MHC IIA fibers in flutamide-treated mice, but faster in EE2-treated mice, indicating that contractile velocity may be affected differently in this fiber type which is commonly expressed in human skeletal muscle. Importantly, these effects were observed in the absence of outcomes previously used to evaluate ER agonists or AR antagonists in rodents including weight of reproductive organs or mammary gland morphology. Our findings indicate that substantial shifts in skeletal muscle function occur in male mice following acute exposures to low doses of a pharmacological ER agonist and an AR antagonist. These results suggest that countermeasures to maintain physical function may be needed early in situations that induce similar ER agonist and AR antagonist conditions.

Keywords:  Flutamide; Hormone; Myosin Heavy Chains; Myosins; Testosterone

DOI:  https://doi.org/10.1210/endocr/bqad132
Curr Protoc. 2023 Aug;3(8): e877

Transcriptional Profiling of Skeletal Muscle Stem Cells After In Vivo Engraftment into a Heterologous Niche Environment.

Felicia Lazure, Darren M Blackburn, Vahab D Soleimani.

  Adult stem cells play a critical role in the maintenance and repair of the organs in which they reside. However, their function is highly dependent on the crosstalk with their niche environment that changes during development and in disease states. The niche provides signals to stem cells to activate, proliferate, self-renew, or remain in quiescence. In skeletal muscle, the niche is perturbed in disease contexts such as aging, muscular dystrophies, and cachexia. Therefore, it is important to develop methods that permit the decoupling of niche-mediated from cell-intrinsic changes that occur in muscle stem cells (MuSCs) in development and disease contexts. With the purpose of determining the effect of the niche environment on the MuSC transcriptome, function, or health, we have coupled an allogeneic stem cell transplantation system, meaning the transplantation of MuSCs from a donor mouse into a recipient host mouse, with Switching Mechanism at 5' End of RNA Template (SMART-Seq) to quantify the effects of the niche on the MuSC transcriptome in vivo. Briefly, MuSCs are isolated from a GFP reporter donor mouse (Pax7-nGFP) and transplanted into the irradiated muscles of immunocompromised allogeneic hosts. The MuSCs are re-isolated by fluorescence-activated cell sorting (FACS) after three weeks of inhabiting the heterologous niche, defined as a niche that is different from their originating niche, and sequencing-ready libraries are created. This method allows for the direct comparison of the transcriptome of stem cells before and after transplantation into a host of a different age, disease status, or genetic background. This method can be used to accurately quantify the direct effect of the niche environment on the stem cell gene expression profile and to decouple cell-intrinsic versus niche-mediated alterations in the stem cell transcriptome. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol: Allogeneic muscle stem cell transplantation.

Keywords:  SMART-Seq; muscle stem cell; niche environment; transcriptomics; transplantation

DOI:  https://doi.org/10.1002/cpz1.877
J Neuromuscul Dis. 2023 Aug 25.

Resistance Exercise Training Rescues Mitochondrial Dysfunction in Skeletal Muscle of Patients with Myotonic Dystrophy Type 1.

Valeria Di Leo, Conor Lawless, Marie-Pier Roussel, Tiago B Gomes, Gráinne S Gorman, Oliver M Russell, Helen A L Tuppen, Elise Duchesne, Amy E Vincent.

   BACKGROUND: Myotonic dystrophy type 1 (DM1) is a dominant autosomal neuromuscular disorder caused by the inheritance of a CTG triplet repeat expansion in the Dystrophia Myotonica Protein Kinase (DMPK) gene. At present, no cure currently exists for DM1 disease.
OBJECTIVE: This study investigates the effects of 12-week resistance exercise training on mitochondrial oxidative phosphorylation in skeletal muscle in a cohort of DM1 patients (n = 11, men) in comparison to control muscle with normal oxidative phosphorylation.
METHODS: Immunofluorescence was used to assess protein levels of key respiratory chain subunits of complex I (CI) and complex IV (CIV), and markers of mitochondrial mass and cell membrane in individual myofibres sampled from muscle biopsies. Using control's skeletal muscle fibers population, we classified each patient's fibers as having normal, low or high levels of CI and CIV and compared the proportions of fibers before and after exercise training. The significance of changes observed between pre- and post-exercise within patients was estimated using a permutation test.
RESULTS: At baseline, DM1 patients present with significantly decreased mitochondrial mass, and isolated or combined CI and CIV deficiency. After resistance exercise training, in most patients a significant increase in mitochondrial mass was observed, and all patients showed a significant increase in CI and/or CIV protein levels. Moreover, improvements in mitochondrial mass were correlated with the one-repetition maximum strength evaluation.
CONCLUSIONS: Remarkably, 12-week resistance exercise training is sufficient to partially rescue mitochondrial dysfunction in DM1 patients, suggesting that the response to exercise is in part be due to changes in mitochondria.

Keywords:  Myotonic dystrophy type 1; mitochondrial dysfunction; myotonic dystrophy type 1 therapy; oxidative phosphorylation deficiency; resistance exercise training; skeletal muscle; strength training

DOI:  https://doi.org/10.3233/JND-230099
Mol Ther Nucleic Acids. 2023 Sep 12. 33 683-697

Disease modeling and gene correction of LGMDR21 iPSCs elucidates the role of POGLUT1 in skeletal muscle maintenance, regeneration, and the satellite cell niche.

Jose L Ortiz-Vitali, Jianbo Wu, Nasa Xu, Annie W Shieh, Nima Niknejad, Megumi Takeuchi, Carmen Paradas, Chunru Lin, Hamed Jafar-Nejad, Robert S Haltiwanger, Sidney H Wang, Radbod Darabi.

  Autosomal recessive limb-girdle muscular dystrophy 21 (LGMDR21) is caused by pathogenic variants in protein O-glucosyltransferase 1 (POGLUT1), which is responsible for O-glucosylation of specific epidermal growth factor (EGF) repeats found in ∼50 mammalian proteins, including Notch receptors. Previous data from patient biopsies indicated that impaired Notch signaling, reduction of muscle stem cells, and accelerated differentiation are probably involved in disease etiopathology. Using patient induced pluripotent stem cells (iPSCs), their corrected isotypes, and control iPSCs, gene expression profiling indicated dysregulation of POGLUT1, NOTCH, muscle development, extracellular matrix (ECM), cell adhesion, and migration as involved pathways. They also exhibited reduced in vitro POGLUT1 enzymatic activity and NOTCH signaling as well as defective myogenesis, proliferation, migration and differentiation. Furthermore, in vivo studies demonstrated significant reductions in engraftment, muscle stem cell formation, PAX7 expression, and maintenance, along with an increased percentage of mislocalized PAX7+ cells in the interstitial space. Gene correction in patient iPSCs using CRISPR-Cas9 nickase led to the rescue of the main in vitro and in vivo phenotypes. These results demonstrate the efficacy of iPSCs and gene correction in disease modeling and rescue of the phenotypes and provide evidence of the involvement of muscle stem cell niche localization, PAX7 expression, and cell migration as possible mechanisms in LGMDR21.

Keywords:  CRISPR-Cas9; LGMDR21; MT: RNA/DNA Editing; POGLUT1; gene correction; iPSCs; muscle stem cells; skeletal muscle

DOI:  https://doi.org/10.1016/j.omtn.2023.07.037
ACS Appl Mater Interfaces. 2023 Aug 31.

Optogenetic Calcium Ion Influx in Myoblasts and Myotubes by Near-Infrared Light Using Upconversion Nanoparticles.

Daisuke Maemura, The Son Le, Mari Takahashi, Kazuaki Matsumura, Shinya Maenosono.

  Bioactuators made of cultured skeletal muscle cells are generally driven by electrical or visible light stimuli. Among these, the technology to control skeletal muscle consisting of myoblasts genetically engineered to express photoreceptor proteins with visible light is very promising, as there is no risk of cell contamination by electrodes, and the skeletal muscle bioactuator can be operated remotely. However, due to the low biopermeability of visible light, it can only be applied to thin skeletal muscle films, making it difficult to realize high-power bioactuators consisting of thick skeletal muscle. To solve this problem, it is desirable to realize thick skeletal muscle bioactuators that can be driven by near-infrared (NIR) light, to which living tissue is highly permeable. In this study, as a promising first step, upconversion nanoparticles (UCNPs) capable of converting NIR light into blue light were bound to C2C12 myoblasts expressing the photoreceptor protein channelrhodopsin-2 (ChR2), and the myoblasts calcium ion (Ca2+) influx was remotely manipulated by NIR light exposure. UCNP-bound myoblasts and UCNP-bound differentiated myotubes were exposed to NIR light, and the intracellular Ca2+ concentrations were measured and compared to myoblasts exposed to blue light. Exposure of the UCNP-bound cells to NIR light was found to be more efficient than exposure to blue light in terms of stimulating Ca2+ influx.

Keywords:  muscle cells; near-infrared light control; optogenetics; photoreceptor protein; upconversion nanoparticle

DOI:  https://doi.org/10.1021/acsami.3c07028
Mol Ther Nucleic Acids. 2023 Sep 12. 33 617-628

Long-term muscle-specific overexpression of DOK7 in mice using AAV9-tMCK-DOK7.

Yu-Ting Huang, Hannah R Crick, Helena Chaytow, Dinja van der Hoorn, Abrar Alhindi, Ross A Jones, Ralph D Hector, Stuart R Cobb, Thomas H Gillingwater.

  Neuromuscular junction (NMJ) dysfunction underlies several diseases, including congenital myasthenic syndromes (CMSs) and motor neuron disease (MND). Molecular pathways governing NMJ stability are therefore of interest from both biological and therapeutic perspectives. Muscle-specific kinase (MuSK) is necessary for the formation and maintenance of post-synaptic elements of the NMJ, and downstream of tyrosine kinases 7 (DOK7) is crucial for activation of the MuSK pathway. Overexpression of DOK7 using AAV9 has been shown to ameliorate neuromuscular pathology in pre-clinical disease models of CMS and MND. However, long-term consequences of DOK7 expression have been sparsely investigated and targeted overexpression of DOK7 in skeletal muscle yet to be established. Here, we developed and characterized a novel AAV9-DOK7 facilitating forced expression of DOK7 under a skeletal muscle-specific promoter. AAV9-tMCK-DOK7 was systemically delivered to newborn mice that were monitored over 6 months. DOK7 overexpression was restricted to skeletal muscles. Body weight, blood biochemistry, and histopathological assessments were unaffected by AAV9-tMCK-DOK7 treatment. In contrast, forced expression of DOK7 resulted in enlargement of both the pre- and post-synaptic components of the NMJ, without causing denervation. We conclude that muscle-specific DOK7 overexpression can be achieved in a safe manner, with the capacity to target NMJs in vivo.

Keywords:  AAV9; DOK7; MT: Delivery strategies; NMJ; gene therapy; mouse; neuromuscular junction

DOI:  https://doi.org/10.1016/j.omtn.2023.07.036
Sci Transl Med. 2023 Aug 30. 15(711): eabh3489

Farnesol prevents aging-related muscle weakness in mice through enhanced farnesylation of Parkin-interacting substrate.

Ju-Hyeon Bae, Areum Jo, Sung Chun Cho, Yun-Il Lee, Tae-In Kam, Chang-Lim You, Hyeon-Ju Jeong, Hyebeen Kim, Myong-Ho Jeong, Yideul Jeong, Young Wan Ha, Yu Seon Kim, Jiwoon Kim, Seung-Hwa Woo, Minseok S Kim, Eui Seok Shin, Sang Ok Song, Hojin Kang, Rin Khang, Soojeong Park, Joobae Park, Valina L Dawson, Ted M Dawson, Sang Chul Park, Joo-Ho Shin, Jong-Sun Kang.

Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a master regulator of mitochondrial biogenesis. Reduced PGC-1α abundance is linked to skeletal muscle weakness in aging or pathological conditions, such as neurodegenerative diseases and diabetes; thus, elevating PGC-1α abundance might be a promising strategy to treat muscle aging. Here, we performed high-throughput screening and identified a natural compound, farnesol, as a potent inducer of PGC-1α. Farnesol administration enhanced oxidative muscle capacity and muscle strength, leading to metabolic rejuvenation in aged mice. Moreover, farnesol treatment accelerated the recovery of muscle injury associated with enhanced muscle stem cell function. The protein expression of Parkin-interacting substrate (PARIS/Zfp746), a transcriptional repressor of PGC-1α, was elevated in aged muscles, likely contributing to PGC-1α reduction. The beneficial effect of farnesol on aged muscle was mediated through enhanced PARIS farnesylation, thereby relieving PARIS-mediated PGC-1α suppression. Furthermore, short-term exercise increased PARIS farnesylation in the muscles of young and aged mice, whereas long-term exercise decreased PARIS expression in the muscles of aged mice, leading to the elevation of PGC-1α. Collectively, the current study demonstrated that the PARIS-PGC-1α pathway is linked to muscle aging and that farnesol treatment can restore muscle functionality in aged mice through increased farnesylation of PARIS.

DOI: https://doi.org/10.1126/scitranslmed.abh3489
Am J Clin Nutr. 2023 Aug 30. pii: S0002-9165(23)66113-1. [Epub ahead of print]

The role of nutrition in the prevention of sarcopenia.

Sian Robinson, Antoneta Granic, Alfonso J Cruz-Jentoft, Avan A Sayer.

  Sarcopenia is a common skeletal muscle disorder, characterised by a loss of muscle mass and impaired muscle function, that is associated with poorer health outcomes. While nutrition is considered an important factor in the aetiology of sarcopenia, the preventive potential of diet - specifically the extent to which differences in habitual patterns of diet and/or nutrient intakes impact on the risk of its development - is poorly understood. This narrative review considered research evidence on dietary patterns and nutrient intakes in mid- (<60 years) and young-older (60-70 years) adulthood, to evaluate how they relate to age-related changes in muscle mass and function. A key finding was that current evidence on adult diet and sarcopenia risk in older age is limited and fragmentary, with different outcomes reported across studies (eg lean mass, strength) and few reporting links to incident diagnosed sarcopenia. As these outcomes are not interchangeable, it challenges collation of the evidence, leaving many gaps in understanding. There is also limited information about adult diet (<70 years) and few longitudinal studies with repeated dietary assessments to enable definition of cumulative exposures across adulthood. However, despite these limitations, findings from dietary patterns studies already provide reasonably consistent messages about the benefits of diets of higher quality in earlier adulthood for later physical performance, although whole diet intervention trials are urgently needed to understand their potential. In comparison, there is little evidence of benefits of higher intakes of individual nutrients in earlier adulthood for later muscle mass and function. While these gaps need to be addressed in future research, there may already be sufficient data to promote messages about diet quality more widely - that 'healthier' diets of higher quality across adulthood, with known benefits for a range of health outcomes, are also linked to effective preservation of muscle mass and function.

Keywords:  Ageing; Diet; Lifecourse; Prevention; Sarcopenia

DOI:  https://doi.org/10.1016/j.ajcnut.2023.08.015
Ageing Res Rev. 2023 Aug 29. pii: S1568-1637(23)00207-6. [Epub ahead of print] 102048

Does Exercise Influence Skeletal Muscle by Modulating Mitochondrial Functions via Regulating MicroRNAs? A Systematic Review.

Yu-Feng Long, Simon Kwoon-Ho Chow, Can Cui, Ronald Man Yeung Wong, Ning Zhang, Ling Qin, Sheung-Wai Law, Wing-Hoi Cheung.

   BACKGROUND: Sarcopenia is the accelerated loss of muscle mass, strength and function. Mitochondrial dysfunction was related to the progression of sarcopenia; meanwhile, microRNAs were regarded as core roles in regulating mitochondrial function. Physical exercise is a well-accepted approach to attenuate sarcopenia, yet very few studies depict the molecular mechanisms. The aim of this systematic review is to explore the potential relationships among physical exercise, mitochondrial function, and microRNAs, which may give new insight for retarding sarcopenia.
METHODS: A systematic literature search was performed in PubMed, Embase and Web of Science. The keywords were combined as "(microRNA OR miR) AND mitochondri* AND muscle AND exercise" and searched in all fields. PRISMA guidelines were followed. Information was extracted from the included studies for review.
RESULTS: In this review, 18 preclinical studies and 5 clinical studies were included. Most of the included studies suggested that effective physical exercise had positive effects on mitochondrial functions by regulating microRNAs. The results showed that 12 microRNAs improved mitochondrial functions, while 18 microRNAs suppressed them. Meanwhile, the results showed that 5 microRNAs improved muscle performance.
CONCLUSIONS: This systematic review provides an up-to-date sequential overview and highlights the potential relationship among exercise, mitochondrial function, and microRNAs in muscle. Meanwhile, evidence revealed that physical exercise can improve muscle performance by up-regulating mitochondrial functions, especially mitochondrial biogenesis, through modulating microRNAs.

Keywords:  microRNA; mitochondrion; muscle; physical exercise

DOI:  https://doi.org/10.1016/j.arr.2023.102048
bioRxiv. 2023 Aug 16. pii: 2023.08.14.553247. [Epub ahead of print]

Agent-based model demonstrates the impact of nonlinear, complex interactions between cytokines on muscle regeneration.

Megan Haase, Tien Comlekoglu, Alexa Petrucciani, Shayn M Peirce, Silvia S Blemker.

Muscle regeneration is a complex process due to dynamic and multiscale biochemical and cellular interactions, making it difficult to determine optimal treatments for muscle injury using experimental approaches alone. To understand the degree to which individual cellular behaviors impact endogenous mechanisms of muscle recovery, we developed an agent-based model (ABM) using the Cellular Potts framework to simulate the dynamic microenvironment of a cross-section of murine skeletal muscle tissue. We referenced more than 100 published studies to define over 100 parameters and rules that dictate the behavior of muscle fibers, satellite stem cells (SSC), fibroblasts, neutrophils, macrophages, microvessels, and lymphatic vessels, as well as their interactions with each other and the microenvironment. We utilized parameter density estimation to calibrate the model to temporal biological datasets describing cross-sectional area (CSA) recovery, SSC, and fibroblast cell counts at multiple time points following injury. The calibrated model was validated by comparison of other model outputs (macrophage, neutrophil, and capillaries counts) to experimental observations. Predictions for eight model perturbations that varied cell or cytokine input conditions were compared to published experimental studies to validate model predictive capabilities. We used Latin hypercube sampling and partial rank correlation coefficient to identify in silico perturbations of cytokine diffusion coefficients and decay rates to enhance CSA recovery. This analysis suggests that combined alterations of specific cytokine decay and diffusion parameters result in greater fibroblast and SSC proliferation compared to individual perturbations with a 13% increase in CSA recovery compared to unaltered regeneration at 28 days. These results enable guided development of therapeutic strategies that similarly alter muscle physiology (i.e. converting ECM-bound cytokines into freely diffusible forms as studied in cancer therapeutics or delivery of exogenous cytokines) during regeneration to enhance muscle recovery after injury.

DOI: https://doi.org/10.1101/2023.08.14.553247
PLoS One. 2023 ;18(8): e0284834

Comparative analysis of the myoglobin gene in whales and humans reveals evolutionary changes in regulatory elements and expression levels.

Charles Sackerson, Vivian Garcia, Nicole Medina, Jessica Maldonado, John Daly, Rachel Cartwright.

Cetacea and other diving mammals have undergone numerous adaptations to their aquatic environment, among them high levels of the oxygen-carrying intracellular hemoprotein myoglobin in skeletal muscles. Hypotheses regarding the mechanisms leading to these high myoglobin levels often invoke the induction of gene expression by exercise, hypoxia, and other physiological gene regulatory pathways. Here we explore an alternative hypothesis: that cetacean myoglobin genes have evolved high levels of transcription driven by the intrinsic developmental mechanisms that drive muscle cell differentiation. We have used luciferase assays in differentiated C2C12 cells to test this hypothesis. Contrary to our hypothesis, we find that the myoglobin gene from the minke whale, Balaenoptera acutorostrata, shows a low level of expression, only about 8% that of humans. This low expression level is broadly shared among cetaceans and artiodactylans. Previous work on regulation of the human gene has identified a core muscle-specific enhancer comprised of two regions, the "AT element" and a C-rich sequence 5' of the AT element termed the "CCAC-box". Analysis of the minke whale gene supports the importance of the AT element, but the minke whale CCAC-box ortholog has little effect. Instead, critical positive input has been identified in a G-rich region 3' of the AT element. Also, a conserved E-box in exon 1 positively affects expression, despite having been assigned a repressive role in the human gene. Last, a novel region 5' of the core enhancer has been identified, which we hypothesize may function as a boundary element. These results illustrate regulatory flexibility during evolution. We discuss the possibility that low transcription levels are actually beneficial, and that evolution of the myoglobin protein toward enhanced stability is a critical factor in the accumulation of high myoglobin levels in adult cetacean muscle tissue.

DOI: https://doi.org/10.1371/journal.pone.0284834
Proc Natl Acad Sci U S A. 2023 Sep 05. 120(36): e2303859120

Myo-differentiation reporter screen reveals NF-Y as an activator of PAX3-FOXO1 in rhabdomyosarcoma.

Martyna W Sroka, Damianos Skopelitis, Marit W Vermunt, Jonathan B Preall, Osama El Demerdash, Larissa M N de Almeida, Kenneth Chang, Raditya Utama, Berkley Gryder, Giuseppina Caligiuri, Diqiu Ren, Benan Nalbant, Joseph P Milazzo, David A Tuveson, Alexander Dobin, Scott W Hiebert, Kristy R Stengel, Roberto Mantovani, Javed Khan, Rahul M Kohli, Junwei Shi, Gerd A Blobel, Christopher R Vakoc.

  Recurrent chromosomal rearrangements found in rhabdomyosarcoma (RMS) produce the PAX3-FOXO1 fusion protein, which is an oncogenic driver and a dependency in this disease. One important function of PAX3-FOXO1 is to arrest myogenic differentiation, which is linked to the ability of RMS cells to gain an unlimited proliferation potential. Here, we developed a phenotypic screening strategy for identifying factors that collaborate with PAX3-FOXO1 to block myo-differentiation in RMS. Unlike most genes evaluated in our screen, we found that loss of any of the three subunits of the Nuclear Factor Y (NF-Y) complex leads to a myo-differentiation phenotype that resembles the effect of inactivating PAX3-FOXO1. While the transcriptomes of NF-Y- and PAX3-FOXO1-deficient RMS cells bear remarkable similarity to one another, we found that these two transcription factors occupy nonoverlapping sites along the genome: NF-Y preferentially occupies promoters, whereas PAX3-FOXO1 primarily binds to distal enhancers. By integrating multiple functional approaches, we map the PAX3 promoter as the point of intersection between these two regulators. We show that NF-Y occupies CCAAT motifs present upstream of PAX3 to function as a transcriptional activator of PAX3-FOXO1 expression in RMS. These findings reveal a critical upstream role of NF-Y in the oncogenic PAX3-FOXO1 pathway, highlighting how a broadly essential transcription factor can perform tumor-specific roles in governing cellular state.

Keywords:  NF-Y; PAX3–FOXO1; muscle; myo-differentiation; rhabdomyosarcoma

DOI:  https://doi.org/10.1073/pnas.2303859120