scholarly journals Muscle-to-Brain Signaling Via Myokines and Myometabolites

2022 ◽  
pp. 1-21
Author(s):  
Mamta Rai ◽  
Fabio Demontis
Keyword(s):  
Skeletal Muscle ◽  
Metabolic Stress ◽  
Brain Diseases ◽  
Unfolded Protein ◽  
Energy Demands ◽  
Age Related ◽  
Lipid Species ◽  
The Central Nervous System ◽  
And Function ◽  
Protein Response

Skeletal muscle health and function are important determinants of systemic metabolic homeostasis and organism-wide responses, including disease outcome. While it is well known that exercise protects the central nervous system (CNS) from aging and disease, only recently this has been found to depend on the endocrine capacity of skeletal muscle. Here, we review muscle-secreted growth factors and cytokines (myokines), metabolites (myometabolites), and other unconventional signals (e.g. bioactive lipid species, enzymes, and exosomes) that mediate muscle-brain and muscle-retina communication and neuroprotection in response to exercise and associated processes, such as the muscle unfolded protein response and metabolic stress. In addition to impacting proteostasis, neurogenesis, and cognitive functions, muscle-brain signaling influences complex brain-dependent behaviors, such as depression, sleeping patterns, and biosynthesis of neurotransmitters. Moreover, myokine signaling adapts feeding behavior to meet the energy demands of skeletal muscle. Contrary to protective myokines induced by exercise and associated signaling pathways, inactivity and muscle wasting may derange myokine expression and secretion and in turn compromise CNS function. We propose that tailoring muscle-to-CNS signaling by modulating myokines and myometabolites may combat age-related neurodegeneration and brain diseases that are influenced by systemic signals.

scholarly journals Two human metabolites rescue a C. elegans model of Alzheimer’s disease via a cytosolic unfolded protein response

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Priyanka Joshi ◽  
Michele Perni ◽  
Ryan Limbocker ◽  
Benedetta Mannini ◽  
Sam Casford ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Unfolded Protein Response ◽  
Neurodegenerative Disorders ◽  
C Elegans ◽  
Unfolded Protein ◽  
Model Of Alzheimer’S Disease ◽  
Age Related ◽  
Parkinson’S Diseases ◽  
Protein Response

AbstractAge-related changes in cellular metabolism can affect brain homeostasis, creating conditions that are permissive to the onset and progression of neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. Although the roles of metabolites have been extensively studied with regard to cellular signaling pathways, their effects on protein aggregation remain relatively unexplored. By computationally analysing the Human Metabolome Database, we identified two endogenous metabolites, carnosine and kynurenic acid, that inhibit the aggregation of the amyloid beta peptide (Aβ) and rescue a C. elegans model of Alzheimer’s disease. We found that these metabolites act by triggering a cytosolic unfolded protein response through the transcription factor HSF-1 and downstream chaperones HSP40/J-proteins DNJ-12 and DNJ-19. These results help rationalise previous observations regarding the possible anti-ageing benefits of these metabolites by providing a mechanism for their action. Taken together, our findings provide a link between metabolite homeostasis and protein homeostasis, which could inspire preventative interventions against neurodegenerative disorders.

scholarly journals Confounding Roles of ER Stress and the Unfolded Protein Response in Skeletal Muscle Atrophy

2021 ◽  
Vol 22 (5) ◽  
pp. 2567
Author(s):  
Yann S. Gallot ◽  
Kyle R. Bohnert
Keyword(s):  
Skeletal Muscle ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Smooth Endoplasmic Reticulum ◽  
Skeletal Muscle Atrophy ◽  
Unfolded Protein ◽  
The Individual ◽  
The Unfolded Protein Response ◽  
Protein Response

Skeletal muscle is an essential organ, responsible for many physiological functions such as breathing, locomotion, postural maintenance, thermoregulation, and metabolism. Interestingly, skeletal muscle is a highly plastic tissue, capable of adapting to anabolic and catabolic stimuli. Skeletal muscle contains a specialized smooth endoplasmic reticulum (ER), known as the sarcoplasmic reticulum, composed of an extensive network of tubules. In addition to the role of folding and trafficking proteins within the cell, this specialized organelle is responsible for the regulated release of calcium ions (Ca2+) into the cytoplasm to trigger a muscle contraction. Under various stimuli, such as exercise, hypoxia, imbalances in calcium levels, ER homeostasis is disturbed and the amount of misfolded and/or unfolded proteins accumulates in the ER. This accumulation of misfolded/unfolded protein causes ER stress and leads to the activation of the unfolded protein response (UPR). Interestingly, the role of the UPR in skeletal muscle has only just begun to be elucidated. Accumulating evidence suggests that ER stress and UPR markers are drastically induced in various catabolic stimuli including cachexia, denervation, nutrient deprivation, aging, and disease. Evidence indicates some of these molecules appear to be aiding the skeletal muscle in regaining homeostasis whereas others demonstrate the ability to drive the atrophy. Continued investigations into the individual molecules of this complex pathway are necessary to fully understand the mechanisms.

scholarly journals Superoxide Anion Production and Bioenergetic Profile in Young and Elderly Human Primary Myoblasts

2018 ◽  
Vol 2018 ◽  
pp. 1-16 ◽  
Author(s):  
Mariangela Marrone ◽  
Rita Maria Laura La Rovere ◽  
Simone Guarnieri ◽  
Ester Sara Di Filippo ◽  
Giovanni Monaco ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Oxidative Phosphorylation ◽  
Energy Demand ◽  
The Elderly ◽  
Compensatory Mechanisms ◽  
Superoxide Anion Production ◽  
Age Related ◽  
Primary Myoblasts ◽  
Production Variability ◽  
And Function

Sarcopenia is the age-related loss of skeletal muscle mass, strength, and function. It is associated with regenerative difficulties by satellite cells, adult muscle stem cells, and alteration of oxidative management, mainly the increase in superoxide anions (O2•−). We aimed to investigate the relation between regenerative deficit in elderly and increase in O2•− production along with mitochondrial alterations. Myoblasts and myotubes from skeletal muscle of young and elderly healthy subjects (27.8 ± 6 and 72.4 ± 6.5 years old) were measured: (1) superoxide dismutase activity and protein content, (2) mitochondrial O2•− production levels, (3) O2•− production variability, and (4) mitochondrial bioenergetic profile. Compared to young myoblasts, elderly myoblasts displayed decreased SOD2 protein expression, elevated mitochondrial O2•− baseline levels, and decreased oxidative phosphorylation and glycolysis. Additionally, elderly versus young myotubes showed elevated mitochondrial O2•− levels when stressed with N-acetyl cysteine or high glucose and higher glycolysis despite showing comparable oxidative phosphorylation levels. Altogether, the elderly may have less metabolic plasticity due to the impaired mitochondrial function caused by O2•−. However, the increased energy demand related to the differentiation process appears to activate compensatory mechanisms for the partial mitochondrial dysfunction.

scholarly journals Effect of Exercise Intensity on Unfolded Protein Response in Skeletal Muscle of Rat

2014 ◽  
Vol 18 (3) ◽  
pp. 211 ◽  
Author(s):  
Kihoon Kim ◽  
Yun-Hye Kim ◽  
Sung-Hye Lee ◽  
Man-Joong Jeon ◽  
So-Young Park ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Unfolded Protein Response ◽  
Exercise Intensity ◽  
Unfolded Protein ◽  
Protein Response

scholarly journals NEUROMUSCULAR CHANGES WITH AGING AND SARCOPENIA

2018 ◽  
pp. 1-3
Author(s):  
B.C. Clark
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Muscle Function ◽  
Skeletal Muscle Mass ◽  
The Past ◽  
Conceptual Definition ◽  
Age Related ◽  
Per Se ◽  
Definition Of ◽  
And Function

Sarcopenia was originally conceptualized as the age-related loss of skeletal muscle mass. Over the ensuing decades, the conceptual definition of sarcopenia has changed to represent a condition in older adults that is characterized by declining muscle mass and function, with “function” most commonly conceived as muscle weakness and/or impaired physical performance (e.g., slow gait speed). Findings over the past 15-years, however, have demonstrated that changes in grip and leg extensor strength are not primarily due to muscle atrophy per se, and that to a large extent, are reflective of declines in the integrity of the nervous system. This article briefly summarizes findings relating to the complex neuromuscular mechanisms that contribute to reductions in muscle function associated with advancing age, and the implications of these findings on the development of effective therapies.

scholarly journals Role of Age-Related Mitochondrial Dysfunction in Sarcopenia

2020 ◽  
Vol 21 (15) ◽  
pp. 5236 ◽  
Author(s):  
Evelyn Ferri ◽  
Emanuele Marzetti ◽  
Riccardo Calvani ◽  
Anna Picca ◽  
Matteo Cesari ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cellular Senescence ◽  
Significant Loss ◽  
Muscle Aging ◽  
Age Related ◽  
Mitochondrial Functions ◽  
Health Quality ◽  
Skeletal Muscle Aging ◽  
And Function

Skeletal muscle aging is associated with a significant loss of skeletal muscle strength and power (i.e., dynapenia), muscle mass and quality of life, a phenomenon known as sarcopenia. This condition affects nearly one-third of the older population and is one of the main factors leading to negative health outcomes in geriatric patients. Notwithstanding the exact mechanisms responsible for sarcopenia are not fully understood, mitochondria have emerged as one of the central regulators of sarcopenia. In fact, there is a wide consensus on the assumption that the loss of mitochondrial integrity in myocytes is the main factor leading to muscle degeneration. Mitochondria are also key players in senescence. It has been largely proven that the modulation of mitochondrial functions can induce the death of senescent cells and that removal of senescent cells improves musculoskeletal health, quality, and function. In this review, the crosstalk among mitochondria, cellular senescence, and sarcopenia will be discussed with the aim to elucidate the role that the musculoskeletal cellular senescence may play in the onset of sarcopenia through the mediation of mitochondria.

scholarly journals Stressed: The Unfolded Protein Response in T Cell Development, Activation, and Function

2019 ◽  
Vol 20 (7) ◽  
pp. 1792 ◽  
Author(s):  
Kyeorda Kemp ◽  
Cody Poe
Keyword(s):  
Endoplasmic Reticulum ◽  
T Cell ◽  
Unfolded Protein Response ◽  
T Cell Development ◽  
Cell Development ◽  
Secretory Cells ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
And Function ◽  
Protein Response

The unfolded protein response (UPR) is a highly conserved pathway that allows cells to respond to stress in the endoplasmic reticulum caused by an accumulation of misfolded and unfolded protein. This is of great importance to secretory cells because, in order for proteins to traffic from the endoplasmic reticulum (ER), they need to be folded appropriately. While a wealth of literature has implicated UPR in immune responses, less attention has been given to the role of UPR in T cell development and function. This review discusses the importance of UPR in T cell development, homeostasis, activation, and effector functions. We also speculate about how UPR may be manipulated in T cells to ameliorate pathologies.

scholarly journals Transient activation of the UPRER is an essential step in the acquisition of pluripotency during reprogramming

2019 ◽  
Vol 5 (4) ◽  
pp. eaaw0025 ◽  
Author(s):  
Milos S. Simic ◽  
Erica A. Moehle ◽  
Robert T. Schinzel ◽  
Franziska K. Lorbeer ◽  
Jonathan J. Halloran ◽  
...  
Keyword(s):  
Cellular Reprogramming ◽  
Epigenetic Landscape ◽  
Form And Function ◽  
Unfolded Protein ◽  
Transient Activation ◽  
Reprogramming Efficiency ◽  
Low Efficiency ◽  
The Unfolded Protein Response ◽  
And Function ◽  
Protein Response

Somatic cells can be reprogrammed into pluripotent stem cells using the Yamanaka transcription factors. Reprogramming requires both epigenetic landscape reshaping and global remodeling of cell identity, structure, basic metabolic processes, and organelle form and function. We hypothesize that variable regulation of the proteostasis network and its influence upon the protein-folding environment within cells and their organelles is responsible for the low efficiency and stochasticity of reprogramming. We find that the unfolded protein response of the endoplasmic reticulum (UPRER), the mitochondrial UPR, and the heat shock response, which ensure proteome quality during stress, are activated during reprogramming. The UPRER is particularly crucial, and its ectopic, transient activation, genetically or pharmacologically, enhances reprogramming. Last, stochastic activation of the UPRER predicts reprogramming efficiency in naïve cells. Thus, the low efficiency and stochasticity of cellular reprogramming are due partly to the inability to properly initiate the UPRER to remodel the ER and its proteome.

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