Metabolic remodeling of dystrophic skeletal muscle reveals biological roles for dystrophin and utrophin in adaptation and plasticity

Regular exercise plays an essential role in maintaining healthy neurocognitive function and central nervous system (CNS) immuno-metabolism in the aging CNS. Physical activity decreases the risk of developing Alzheimer's Disease (AD), is associated with better AD prognosis, and positively affects cognitive function in AD patients. Skeletal muscle is an important secretory organ, communicating proteotoxic and metabolic stress to distant tissues, including the CNS, through the secretion of bioactive molecules collectively known as myokines. Skeletal muscle undergoes significant physical and metabolic remodeling during exercise, including alterations in myokine expression profiles. This suggests that changes in myokine and myometabolite secretion may underlie the well-documented benefits of exercise in AD. However, to date, very few studies have focused on specific alterations in skeletal muscle-originating secreted factors and their potential neuroprotective effects in AD. In this review, we discuss exercise therapy for AD prevention and intervention, and propose the use of circulating myokines as novel therapeutic tools for modifying AD progression.

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Skeletal muscle thermogenesis enables aquatic life in the smallest marine mammal

Science ◽

10.1126/science.abf4557 ◽

2021 ◽

Vol 373 (6551) ◽

pp. 223-225

Author(s):

Traver Wright ◽

Randall W. Davis ◽

Heidi C. Pearson ◽

Michael Murray ◽

Melinda Sheffield-Moore

Keyword(s):

Skeletal Muscle ◽

Metabolic Rate ◽

Basal Metabolic Rate ◽

Tissue Level ◽

Whole Body ◽

Sea Otter ◽

Aquatic Life ◽

Respiratory Capacity ◽

Metabolic Remodeling ◽

Whole Body Metabolism

Basal metabolic rate generally scales with body mass in mammals, and variation from predicted levels indicates adaptive metabolic remodeling. As a thermogenic adaptation for living in cool water, sea otters have a basal metabolic rate approximately three times that of the predicted rate; however, the tissue-level source of this hypermetabolism is unknown. Because skeletal muscle is a major determinant of whole-body metabolism, we characterized respiratory capacity and thermogenic leak in sea otter muscle. Compared with that of previously sampled mammals, thermogenic muscle leak capacity was elevated and could account for sea otter hypermetabolism. Muscle respiratory capacity was modestly elevated and reached adult levels in neonates. Premature metabolic development and high leak rate indicate that sea otter muscle metabolism is regulated by thermogenic demand and is the source of basal hypermetabolism.

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The Basic Science of Metabolism in Pulmonary Arterial Hypertension

Advances in Pulmonary Hypertension ◽

10.21693/1933-088x-17.3.95 ◽

2018 ◽

Vol 17 (3) ◽

pp. 95-102 ◽

Cited By ~ 5

Author(s):

Andrea L. Frump ◽

Tim Lahm

Keyword(s):

Skeletal Muscle ◽

Right Heart Failure ◽

Inflammatory Cells ◽

Therapeutic Interventions ◽

Pulmonary Vasculature ◽

Metabolic Theory ◽

Metabolic Defects ◽

Metabolic Remodeling ◽

Common Etiology ◽

The Right

Pulmonary hypertension (PH) encompasses a group of progressive and incurable cardiopulmonary disorders characterized by pulmonary vascular remodeling and increased mean pulmonary artery pressure leading to right heart failure. Emerging data suggest a common etiology for the reported diverse molecular and physiological abnormalities observed in the pulmonary vasculature: the metabolic theory of PH. This theory proposes that aberrations in metabolism and mitochondrial function are a major underlying cause for the cellular and organ level PH phenotype. Additionally, the metabolic theory of PH provides a rationale for the observed metabolic defects in other organs and systems outside of the pulmonary vasculature, including the right ventricle (RV), immune system, and skeletal muscle. However, whether these metabolic changes are driving disease and the timing and extent of these aberrations are still unknown. This review highlights: 1) key examples of metabolic alterations in the pulmonary vasculature, RV, inflammatory cells, and skeletal muscle; 2) examples of promising therapeutic interventions directly modifying metabolism; and 3) key remaining questions about the role of metabolic remodeling in PH.

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The transcriptional coactivator PGC-1 is dispensable for chronic overload-induced skeletal muscle hypertrophy and metabolic remodeling

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1312039110 ◽

2013 ◽

Vol 110 (50) ◽

pp. 20314-20319 ◽

Cited By ~ 33

Author(s):

J. Perez-Schindler ◽

S. Summermatter ◽

G. Santos ◽

F. Zorzato ◽

C. Handschin

Keyword(s):

Skeletal Muscle ◽

Muscle Hypertrophy ◽

Transcriptional Coactivator ◽

Skeletal Muscle Hypertrophy ◽

Metabolic Remodeling

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Brief intense interval exercise activates AMPK and p38 MAPK signaling and increases the expression of PGC-1α in human skeletal muscle

Journal of Applied Physiology ◽

10.1152/japplphysiol.90880.2008 ◽

2009 ◽

Vol 106 (3) ◽

pp. 929-934 ◽

Cited By ~ 224

Author(s):

Martin J. Gibala ◽

Sean L. McGee ◽

Andrew P. Garnham ◽

Kirsten F. Howlett ◽

Rodney J. Snow ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

P38 Mapk ◽

Mitochondrial Biogenesis ◽

Human Skeletal Muscle ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Acid Oxidation ◽

Interval Exercise ◽

Metabolic Remodeling

From a cell signaling perspective, short-duration intense muscular work is typically associated with resistance training and linked to pathways that stimulate growth. However, brief repeated sessions of sprint or high-intensity interval exercise induce rapid phenotypic changes that resemble traditional endurance training. We tested the hypothesis that an acute session of intense intermittent cycle exercise would activate signaling cascades linked to mitochondrial biogenesis in human skeletal muscle. Biopsies (vastus lateralis) were obtained from six young men who performed four 30-s “all out” exercise bouts interspersed with 4 min of rest (<80 kJ total work). Phosphorylation of AMP-activated protein kinase (AMPK; subunits α1 and α2) and the p38 mitogen-activated protein kinase (MAPK) was higher ( P ≤ 0.05) immediately after bout 4 vs. preexercise. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) mRNA was increased approximately twofold above rest after 3 h of recovery ( P ≤ 0.05); however, PGC-1α protein content was unchanged. In contrast, phosphorylation of protein kinase B/Akt (Thr308 and Ser473) tended to decrease, and downstream targets linked to hypertrophy (p70 ribosomal S6 kinase and 4E binding protein 1) were unchanged after exercise and recovery. We conclude that signaling through AMPK and p38 MAPK to PGC-1α may explain in part the metabolic remodeling induced by low-volume intense interval exercise, including mitochondrial biogenesis and an increased capacity for glucose and fatty acid oxidation.

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Metabolic Remodeling in Skeletal Muscle Atrophy as a Therapeutic Target

Metabolites ◽

10.3390/metabo11080517 ◽

2021 ◽

Vol 11 (8) ◽

pp. 517

Author(s):

Alessandra Renzini ◽

Carles Sánchez Riera ◽

Isidora Minic ◽

Chiara D’Ercole ◽

Biliana Lozanoska-Ochser ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Therapeutic Target ◽

Muscle Wasting ◽

Muscle Metabolism ◽

Skeletal Muscle Atrophy ◽

Molecular Signaling ◽

Nutritional Interventions ◽

Metabolic Remodeling ◽

External Causes

Skeletal muscle is a highly responsive tissue, able to remodel its size and metabolism in response to external demand. Muscle fibers can vary from fast glycolytic to slow oxidative, and their frequency in a specific muscle is tightly regulated by fiber maturation, innervation, or external causes. Atrophic conditions, including aging, amyotrophic lateral sclerosis, and cancer-induced cachexia, differ in the causative factors and molecular signaling leading to muscle wasting; nevertheless, all of these conditions are characterized by metabolic remodeling, which contributes to the pathological progression of muscle atrophy. Here, we discuss how changes in muscle metabolism can be used as a therapeutic target and review the evidence in support of nutritional interventions and/or physical exercise as tools for counteracting muscle wasting in atrophic conditions.

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Double-blind study of metaxalone; use as skeletal-muscle relaxant

JAMA ◽

10.1001/jama.195.6.479 ◽

1966 ◽

Vol 195 (6) ◽

pp. 479-480 ◽

Cited By ~ 3

Author(s):

S. Diamond

Keyword(s):

Skeletal Muscle ◽

Muscle Relaxant ◽

Blind Study ◽

Double Blind Study ◽

Double Blind ◽

Skeletal Muscle Relaxant

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Endotoxin Alteration of the Mucopolysaccharide Blood Vessel Coating in Rats

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100050755 ◽

1974 ◽

Vol 32 ◽

pp. 148-149

Author(s):

D. E. Philpott ◽

A. Takahashi

Keyword(s):

Skeletal Muscle ◽

Endothelial Cells ◽

Salivary Gland ◽

Carotid Artery ◽

Basement Membrane ◽

Coronary Vessels ◽

Ruthenium Red ◽

E Coli ◽

Old Rats ◽

The Brain

Two month, eight month and two year old rats were treated with 10 or 20 mg/kg of E. Coli endotoxin I. P. The eight month old rats proved most resistant to the endotoxin. During fixation the aorta, carotid artery, basil arartery of the brain, coronary vessels of the heart, inner surfaces of the heart chambers, heart and skeletal muscle, lung, liver, kidney, spleen, brain, retina, trachae, intestine, salivary gland, adrenal gland and gingiva were treated with ruthenium red or alcian blue to preserve the mucopolysaccharide (MPS) coating. Five, 8 and 24 hrs of endotoxin treatment produced increasingly marked capillary damage, disappearance of the MPS coating, edema, destruction of endothelial cells and damage to the basement membrane in the liver, kidney and lung.

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Ultra-Rapid Freezing of Isolated Skeletal Muscle Fibers

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100080316 ◽

1977 ◽

Vol 35 ◽

pp. 576-577

Author(s):

Joachim R. Sommer ◽

Nancy R. Wallace

Keyword(s):

Skeletal Muscle ◽

Sarcoplasmic Reticulum ◽

Granular Material ◽

Nuclear Envelope ◽

Intracellular Calcium ◽

Ruthenium Red ◽

Threshold Concentration ◽

Rapid Freezing ◽

Frog Skeletal Muscle ◽

Electrical Isolation

After Howell (1) had shown that ruthenium red treatment of fixed frog skeletal muscle caused collapse of the intermediate cisternae of the sarcoplasmic reticulum (SR), forming a pentalaminate structure by obi iterating the SR lumen, we demonstrated that the phenomenon involves the entire SR including the nuclear envelope and that it also occurs after treatment with other cations, including calcium (2,3,4).From these observations we have formulated a hypothesis which states that intracellular calcium taken up by the SR at the end of contraction causes the M rete to collapse at a certain threshold concentration as the first step in a subsequent centrifugal zippering of the free SR toward the junctional SR (JSR). This would cause a) bulk transport of SR contents, such as calcium and granular material (4) into the JSR and, b) electrical isolation of the free SR from the JSR.

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