Mitochondrial pathways in sarcopenia of aging and disuse muscle atrophy

Abstract Muscle loss during aging and disuse is a highly prevalent and disabling condition, but knowledge about cellular pathways mediating muscle atrophy is still limited. Given the postmitotic nature of skeletal myocytes, the maintenance of cellular homeostasis relies on the efficiency of cellular quality control mechanisms. In this scenario, alterations in mitochondrial function are considered a major factor underlying sarcopenia and muscle atrophy. Damaged mitochondria are not only less bioenergetically efficient, but also generate increased amounts of reactive oxygen species, interfere with cellular quality control mechanisms, and display a greater propensity to trigger apoptosis. Thus, mitochondria stand at the crossroad of signaling pathways that regulate skeletal myocyte function and viability. Studies on these pathways have sometimes provided unexpected and counterintuitive results, which suggests that they are organized into a complex, heterarchical network that is currently insufficiently understood. Untangling the complexity of such a network will likely provide clinicians with novel and highly effective therapeutics to counter the muscle loss associated with aging and disuse. In this review, we summarize the current knowledge on the mechanisms whereby mitochondrial dysfunction intervenes in the pathogenesis of sarcopenia and disuse atrophy, and highlight the prospect of targeting specific processes to treat these conditions.

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Intra- and Intercellular Quality Control Mechanisms of Mitochondria

10.20944/preprints201712.0008.v1 ◽

2017 ◽

Author(s):

Yoshimitsu Kiriyama ◽

Hiromi Nochi

Keyword(s):

Quality Control ◽

Cell Death ◽

Extracellular Vesicles ◽

Mitochondrial Function ◽

Current Knowledge ◽

Control Mechanisms ◽

Tunneling Nanotubes ◽

Cellular Homeostasis

Mitochondria function to generate ATP and also play important roles in cellular homeostasis, signaling, apoptosis, autophagy, and metabolism. The loss of mitochondrial function results in cell death and various types of diseases. Therefore, quality control of mitochondria via intra- and intercellular pathways is crucial. Intracellular quality control consists of biogenesis, fusion and fission, and degradation of mitochondria in the cell, whereas intercellular quality control involves tunneling nanotubes and extracellular vesicles. In this review, we outline the current knowledge on the intra- and intercellular quality control mechanisms of mitochondria.

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Calpain and caspase-3 play required roles in immobilization-induced limb muscle atrophy

Journal of Applied Physiology ◽

10.1152/japplphysiol.00925.2012 ◽

2013 ◽

Vol 114 (10) ◽

pp. 1482-1489 ◽

Cited By ~ 50

Author(s):

Erin E. Talbert ◽

Ashley J. Smuder ◽

Kisuk Min ◽

Oh Sung Kwon ◽

Scott K. Powers

Keyword(s):

Muscle Atrophy ◽

Caspase 3 ◽

Respiratory Muscles ◽

Ubiquitin Proteasome System ◽

Type I ◽

Disuse Atrophy ◽

Limb Muscle ◽

Disuse Muscle Atrophy ◽

Ubiquitin Proteasome ◽

Rat Soleus Muscle

Prolonged skeletal muscle inactivity results in a rapid decrease in fiber size, primarily due to accelerated proteolysis. Although several proteases are known to contribute to disuse muscle atrophy, the ubiquitin proteasome system is often considered the most important proteolytic system during many conditions that promote muscle wasting. Emerging evidence suggests that calpain and caspase-3 may also play key roles in inactivity-induced atrophy of respiratory muscles, but it remains unknown if these proteases are essential for disuse atrophy in limb skeletal muscles. Therefore, we tested the hypothesis that activation of both calpain and caspase-3 is required for locomotor muscle atrophy induced by hindlimb immobilization. Seven days of immobilization (i.e., limb casting) promoted significant atrophy in type I muscle fibers of the rat soleus muscle. Independent pharmacological inhibition of calpain or caspase-3 prevented this casting-induced atrophy. Interestingly, inhibition of calpain activity also prevented caspase-3 activation, and, conversely, inhibition of caspase-3 prevented calpain activation. These findings indicate that a regulatory cross talk exists between these proteases and provide the first evidence that the activation of calpain and caspase-3 is required for inactivity-induced limb muscle atrophy.

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Muscle Atrophy After ACL Injury: Implications for Clinical Practice

Sports Health A Multidisciplinary Approach ◽

10.1177/1941738120944256 ◽

2020 ◽

Vol 12 (6) ◽

pp. 579-586

Author(s):

Lindsey K. Lepley ◽

Steven M. Davi ◽

Julie P. Burland ◽

Adam S. Lepley

Keyword(s):

Clinical Review ◽

Muscle Mass ◽

Muscle Atrophy ◽

Cruciate Ligament ◽

Muscle Loss ◽

Disuse Atrophy ◽

Tissue Quality ◽

Level Of Evidence ◽

Joint Injury ◽

Inducing Factors

Context: Distinct from the muscle atrophy that develops from inactivity or disuse, atrophy that occurs after traumatic joint injury continues despite the patient being actively engaged in exercise. Recognizing the multitude of factors and cascade of events that are present and negatively influence the regulation of muscle mass after traumatic joint injury will likely enable clinicians to design more effective treatment strategies. To provide sports medicine practitioners with the best strategies to optimize muscle mass, the purpose of this clinical review is to discuss the predominant mechanisms that control muscle atrophy for disuse and posttraumatic scenarios, and to highlight how they differ. Evidence Acquisition: Articles that reported on disuse atrophy and muscle atrophy after traumatic joint injury were collected from peer-reviewed sources available on PubMed (2000 through December 2019). Search terms included the following: disuse muscle atrophy OR disuse muscle mass OR anterior cruciate ligament OR ACL AND mechanism OR muscle loss OR atrophy OR neurological disruption OR rehabilitation OR exercise. Study Design: Clinical review. Level of Evidence: Level 5. Results: We highlight that (1) muscle atrophy after traumatic joint injury is due to a broad range of atrophy-inducing factors that are resistant to standard resistance exercises and need to be effectively targeted with treatments and (2) neurological disruptions after traumatic joint injury uncouple the nervous system from muscle tissue, contributing to a more complex manifestation of muscle loss as well as degraded tissue quality. Conclusion: Atrophy occurring after traumatic joint injury is distinctly different from the muscle atrophy that develops from disuse and is likely due to the broad range of atrophy-inducing factors that are present after injury. Clinicians must challenge the standard prescriptive approach to combating muscle atrophy from simply prescribing physical activity to targeting the neurophysiological origins of muscle atrophy after traumatic joint injury.

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Various Jobs of Proteolytic Enzymes in Skeletal Muscle during Unloading: Facts and Speculations

Journal of Biomedicine and Biotechnology ◽

10.1155/2012/493618 ◽

2012 ◽

Vol 2012 ◽

pp. 1-15 ◽

Cited By ~ 21

Author(s):

E. V. Kachaeva ◽

B. S. Shenkman

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Skeletal Muscles ◽

Proteolytic Enzymes ◽

Disuse Atrophy ◽

Muscle Degeneration ◽

Muscle Adaptation ◽

Signaling Systems ◽

Disuse Muscle Atrophy ◽

Postural Muscles

Skeletal muscles, namely, postural muscles, as soleus, suffer from atrophy under disuse. Muscle atrophy development caused by unloading differs from that induced by denervation or other stimuli. Disuse atrophy is supposed to be the result of shift of protein synthesis/proteolysis balance towards protein degradation increase. Maintaining of the balance involves many systems of synthesis and proteolysis, whose activation leads to muscle adaptation to disuse rather than muscle degeneration. Here, we review recent data on activity of signaling systems involved in muscle atrophy development under unloading and muscle adaptation to the lack of support.

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Mitochondrial Protein Quality Control Mechanisms

Genes ◽

10.3390/genes11050563 ◽

2020 ◽

Vol 11 (5) ◽

pp. 563 ◽

Cited By ~ 4

Author(s):

Pooja Jadiya ◽

Dhanendra Tomar

Keyword(s):

Quality Control ◽

Protein Import ◽

Protein Quality ◽

Current Knowledge ◽

Mitochondrial Protein ◽

Protein Quality Control ◽

Redox Balance ◽

Ubiquitin Proteasome System ◽

Control Mechanisms ◽

Mitochondrial Proteome

Mitochondria serve as a hub for many cellular processes, including bioenergetics, metabolism, cellular signaling, redox balance, calcium homeostasis, and cell death. The mitochondrial proteome includes over a thousand proteins, encoded by both the mitochondrial and nuclear genomes. The majority (~99%) of proteins are nuclear encoded that are synthesized in the cytosol and subsequently imported into the mitochondria. Within the mitochondria, polypeptides fold and assemble into their native functional form. Mitochondria health and integrity depend on correct protein import, folding, and regulated turnover termed as mitochondrial protein quality control (MPQC). Failure to maintain these processes can cause mitochondrial dysfunction that leads to various pathophysiological outcomes and the commencement of diseases. Here, we summarize the current knowledge about the role of different MPQC regulatory systems such as mitochondrial chaperones, proteases, the ubiquitin-proteasome system, mitochondrial unfolded protein response, mitophagy, and mitochondria-derived vesicles in the maintenance of mitochondrial proteome and health. The proper understanding of mitochondrial protein quality control mechanisms will provide relevant insights to treat multiple human diseases.

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Cytosolic protein quality control machinery: Interactions of Hsp70 with a network of co-chaperones and substrates

Experimental Biology and Medicine ◽

10.1177/1535370221999812 ◽

2021 ◽

pp. 153537022199981

Author(s):

Chamithi Karunanayake ◽

Richard C Page

Keyword(s):

Quality Control ◽

Protein Quality ◽

Protein Quality Control ◽

Structural Features ◽

Cellular Protein ◽

Mechanisms Of Action ◽

Control Mechanisms ◽

Nucleotide Exchange ◽

Domain Organization ◽

Nucleotide Exchange Factors

The chaperone heat shock protein 70 (Hsp70) and its network of co-chaperones serve as a central hub of cellular protein quality control mechanisms. Domain organization in Hsp70 dictates ATPase activity, ATP dependent allosteric regulation, client/substrate binding and release, and interactions with co-chaperones. The protein quality control activities of Hsp70 are classified as foldase, holdase, and disaggregase activities. Co-chaperones directly assisting protein refolding included J domain proteins and nucleotide exchange factors. However, co-chaperones can also be grouped and explored based on which domain of Hsp70 they interact. Here we discuss how the network of cytosolic co-chaperones for Hsp70 contributes to the functions of Hsp70 while closely looking at their structural features. Comparison of domain organization and the structures of co-chaperones enables greater understanding of the interactions, mechanisms of action, and roles played in protein quality control.

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COVID-19 Brings Data Equity Challenges to the Fore

Digital Government: Research and Practice (DGOV) ◽

10.1145/3440889 ◽

2021 ◽

Author(s):

H.V. Jagadish ◽

Julia Stoyanovich ◽

Bill Howe

Keyword(s):

Quality Control ◽

Government Policy ◽

Data Driven ◽

Contact Tracing ◽

Control Mechanisms ◽

Sources Of Information ◽

Decision Systems ◽

Physical Resources ◽

Multiple Levels ◽

Data Driven Decisions

The COVID-19 pandemic is compelling us to make crucial data-driven decisions quickly, bringing together diverse and unreliable sources of information without the usual quality control mechanisms we may employ. These decisions are consequential at multiple levels: they can inform local, state and national government policy, be used to schedule access to physical resources such as elevators and workspaces within an organization, and inform contact tracing and quarantine actions for individuals. In all these cases, significant inequities are likely to arise, and to be propagated and reinforced by data-driven decision systems. In this article, we propose a framework, called FIDES, for surfacing and reasoning about data equity in these systems.

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The DEAH helicase DHX36 and its role in G-quadruplex-dependent processes

Biological Chemistry ◽

10.1515/hsz-2020-0292 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Philipp Schult ◽

Katrin Paeschke

Keyword(s):

Current Knowledge ◽

Future Research ◽

Transcriptional Level ◽

Cellular Functions ◽

Multiple Functions ◽

Open Questions ◽

G Quadruplex ◽

Cellular Pathways ◽

Nucleic Acid Structures ◽

Dependent Processes

AbstractDHX36 is a member of the DExD/H box helicase family, which comprises a large number of proteins involved in various cellular functions. Recently, the function of DHX36 in the regulation of G-quadruplexes (G4s) was demonstrated. G4s are alternative nucleic acid structures, which influence many cellular pathways on a transcriptional and post-transcriptional level. In this review we provide an overview of the current knowledge about DHX36 structure, substrate specificity, and mechanism of action based on the available models and crystal structures. Moreover, we outline its multiple functions in cellular homeostasis, immunity, and disease. Finally, we discuss the open questions and provide potential directions for future research.

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Limited ER quality control for GPI-anchored proteins

The Journal of Cell Biology ◽

10.1083/jcb.201602010 ◽

2016 ◽

Vol 213 (6) ◽

pp. 693-704 ◽

Cited By ~ 22

Author(s):

Natalia Sikorska ◽

Leticia Lemus ◽

Auxiliadora Aguilera-Romero ◽

Javier Manzano-Lopez ◽

Howard Riezman ◽

...

Keyword(s):

Quality Control ◽

Endoplasmic Reticulum ◽

Protein Folding ◽

Misfolded Proteins ◽

Control Mechanisms ◽

Gpi Anchor ◽

Er Quality Control ◽

Entire Class ◽

Er Export ◽

Export Signal

Endoplasmic reticulum (ER) quality control mechanisms target terminally misfolded proteins for ER-associated degradation (ERAD). Misfolded glycophosphatidylinositol-anchored proteins (GPI-APs) are, however, generally poor ERAD substrates and are targeted mainly to the vacuole/lysosome for degradation, leading to predictions that a GPI anchor sterically obstructs ERAD. Here we analyzed the degradation of the misfolded GPI-AP Gas1* in yeast. We could efficiently route Gas1* to Hrd1-dependent ERAD and provide evidence that it contains a GPI anchor, ruling out that a GPI anchor obstructs ERAD. Instead, we show that the normally decreased susceptibility of Gas1* to ERAD is caused by canonical remodeling of its GPI anchor, which occurs in all GPI-APs and provides a protein-independent ER export signal. Thus, GPI anchor remodeling is independent of protein folding and leads to efficient ER export of even misfolded species. Our data imply that ER quality control is limited for the entire class of GPI-APs, many of them being clinically relevant.

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