Skeletal muscle pathology in endurance athletes with acquired training intolerance

Aim: The maintenance of healthy and functional mitochondria is the result of a complex mitochondrial turnover and herein quality-control program which includes both mitochondrial biogenesis and autophagy of mitochondria. The aim of this study was to examine the effect of an intensified training load on skeletal muscle mitochondrial quality control in relation to changes in mitochondrial oxidative capacity, maximal oxygen consumption and performance in highly trained endurance athletes. Methods: 27 elite endurance athletes performed high intensity interval exercise followed by moderate intensity continuous exercise 3 days per week for 4 weeks in addition to their usual volume of training. Mitochondrial oxidative capacity, abundance of mitochondrial proteins, markers of autophagy and antioxidant capacity of skeletal muscle were assessed in skeletal muscle biopsies before and after the intensified training period. Results: The intensified training period increased several autophagy markers suggesting an increased turnover of mitochondrial and cytosolic proteins. In permeabilized muscle fibers, mitochondrial respiration was ~20 % lower after training although some markers of mitochondrial density increased by 5-50%, indicative of a reduced mitochondrial quality by the intensified training intervention. The antioxidative proteins UCP3, ANT1, and SOD2 were increased after training, whereas we found an inactivation of aconitase. In agreement with the lower aconitase activity, the amount of mitochondrial LON protease that selectively degrades oxidized aconitase, was doubled. Conclusion: Together, this suggests that mitochondrial respiratory function is impaired during the initial recovery from a period of intensified endurance training while mitochondrial quality control is slightly activated in highly trained skeletal muscle.

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Exercise-induced angiogenesis-related growth and transcription factors in skeletal muscle and their modification in muscle pathology

Frontiers in Bioscience ◽

10.2741/a595 ◽

2001 ◽

Vol 6 (3) ◽

pp. d75-89 ◽

Cited By ~ 11

Author(s):

Thomas Gustafsson

Keyword(s):

Skeletal Muscle ◽

Transcription Factors ◽

Muscle Pathology ◽

Exercise Induced

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Chronic heart failure with diabetes mellitus is characterized by a severe skeletal muscle pathology

Journal of Cachexia Sarcopenia and Muscle ◽

10.1002/jcsm.12515 ◽

2020 ◽

Vol 11 (2) ◽

pp. 394-404 ◽

Cited By ~ 5

Author(s):

Jack O. Garnham ◽

Lee D. Roberts ◽

Ever Espino‐Gonzalez ◽

Anna Whitehead ◽

Peter P. Swoboda ◽

...

Keyword(s):

Diabetes Mellitus ◽

Heart Failure ◽

Skeletal Muscle ◽

Chronic Heart Failure ◽

Muscle Pathology

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The Expanding Clinical Universe of Polyglutamine Disease

The Neuroscientist ◽

10.1177/1073858418822993 ◽

2019 ◽

Vol 25 (5) ◽

pp. 512-520 ◽

Cited By ~ 5

Author(s):

Shanshan Huang ◽

Suiqiang Zhu ◽

Xiao-Jiang Li ◽

Shihua Li

Keyword(s):

Skeletal Muscle ◽

Muscular Atrophy ◽

The Body ◽

Spinocerebellar Ataxia Type ◽

Muscle Pathology ◽

Peripheral Tissues ◽

Therapeutic Implications ◽

Polyq Disease ◽

Spinocerebellar Ataxia Type 17 ◽

Polyq Diseases

Polyglutamine (polyQ) diseases are a group of hereditary neurodegenerative disorders caused by expansion of unstable polyQ repeats in their associated disease proteins. To date, the pathogenesis of each disease remains poorly understood, and there are no effective treatments. Growing evidence has indicated that, in addition to neurodegeneration, polyQ-expanded proteins can cause a wide array of abnormalities in peripheral tissues. Indeed, polyQ-expanded proteins are ubiquitously expressed throughout the body and can affect the function of both the central nervous system (CNS) and peripheral tissues. The peripheral effects of polyQ disease proteins include muscle wasting and reduced muscle strength in patients or animal models of spinal and bulbar muscular atrophy (SBMA), Huntington’s disease (HD), dentatorubral-pallidoluysian atrophy (DRPLA), and spinocerebellar ataxia type 17 (SCA17). Since skeletal muscle pathology can reflect disease progression and is more accessible for treatment than neurodegeneration in the CNS, understanding how polyQ disease proteins affect skeletal muscle will help elucidate disease mechanisms and the development of new therapeutics. In this review, we focus on important findings in terms of skeletal muscle pathology in polyQ diseases and also discuss the potential mechanisms underlying the major peripheral effects of polyQ disease proteins, as well as their therapeutic implications.

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Mechanisms of altered skeletal muscle action potentials in the R6/2 mouse model of Huntington’s disease

AJP Cell Physiology ◽

10.1152/ajpcell.00153.2020 ◽

2020 ◽

Vol 319 (1) ◽

pp. C218-C232 ◽

Cited By ~ 1

Author(s):

Daniel R. Miranda ◽

Eric Reed ◽

Abdulrahman Jama ◽

Michael Bottomley ◽

Hongmei Ren ◽

...

Keyword(s):

Skeletal Muscle ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Decay Time ◽

Motor Dysfunction ◽

Peak Amplitude ◽

Repetitive Firing ◽

Muscle Pathology ◽

Mrna Levels ◽

Electrode Current

Huntington’s disease (HD) patients suffer from progressive and debilitating motor dysfunction for which only palliative treatment is currently available. Previously, we discovered reduced skeletal muscle Cl− channel (ClC-1) and inwardly rectifying K+ channel (Kir) currents in R6/2 HD transgenic mice. To further investigate the role of ClC-1 and Kir currents in HD skeletal muscle pathology, we measured the effect of reduced ClC-1 and Kir currents on action potential (AP) repetitive firing in R6/2 mice using a two-electrode current clamp. We found that R6/2 APs had a significantly lower peak amplitude, depolarized maximum repolarization, and prolonged decay time compared with wild type (WT). Of these differences, only the maximum repolarization was accounted for by the reduction in ClC-1 and Kir currents, indicating the presence of additional ion channel defects. We found that both KV1.5 and KV3.4 mRNA levels were significantly reduced in R6/2 skeletal muscle compared with WT, which explains the prolonged decay time of R6/2 APs. Overall, we found that APs in WT and R6/2 muscle significantly and progressively change during activity to maintain peak amplitude despite buildup of Na+ channel inactivation. Even with this resilience, the persistently reduced peak amplitude of R6/2 APs is expected to result in earlier fatigue and may help explain the motor impersistence experienced by HD patients. This work lays the foundation to link electrical changes to force generation defects in R6/2 HD mice and to examine the regulatory events controlling APs in WT muscle.

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Overexpression of Galgt2 in skeletal muscle prevents injury resulting from eccentric contractions in both mdx and wild-type mice

AJP Cell Physiology ◽

10.1152/ajpcell.00456.2008 ◽

2009 ◽

Vol 296 (3) ◽

pp. C476-C488 ◽

Cited By ~ 53

Author(s):

Paul T. Martin ◽

Rui Xu ◽

Louise R. Rodino-Klapac ◽

Elaine Oglesbay ◽

Marybeth Camboni ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscular Dystrophy ◽

Transgenic Mice ◽

Skeletal Muscles ◽

Eccentric Contractions ◽

Cytotoxic T Cell ◽

Muscle Pathology ◽

Mdx Mice ◽

Specific Force ◽

Wild Type

The cytotoxic T cell (CT) GalNAc transferase, or Galgt2, is a UDP-GalNAc:β1,4- N-acetylgalactosaminyltransferase that is localized to the neuromuscular synapse in adult skeletal muscle, where it creates the synaptic CT carbohydrate antigen {GalNAcβ1,4[NeuAc(orGc)α2, 3]Galβ1,4GlcNAcβ-}. Overexpression of Galgt2 in the skeletal muscles of transgenic mice inhibits the development of muscular dystrophy in mdx mice, a model for Duchenne muscular dystrophy. Here, we provide physiological evidence as to how Galgt2 may inhibit the development of muscle pathology in mdx animals. Both Galgt2 transgenic wild-type and mdx skeletal muscles showed a marked improvement in normalized isometric force during repetitive eccentric contractions relative to nontransgenic littermates, even using a paradigm where nontransgenic muscles had force reductions of 95% or more. Muscles from Galgt2 transgenic mice, however, showed a significant decrement in normalized specific force and in hindlimb and forelimb grip strength at some ages. Overexpression of Galgt2 in muscles of young adult mdx mice, where Galgt2 has no effect on muscle size, also caused a significant decrease in force drop during eccentric contractions and increased normalized specific force. A comparison of Galgt2 and microdystrophin overexpression using a therapeutically relevant intravascular gene delivery protocol showed Galgt2 was as effective as microdystrophin at preventing loss of force during eccentric contractions. These experiments provide a mechanism to explain why Galgt2 overexpression inhibits muscular dystrophy in mdx muscles. That overexpression also prevents loss of force in nondystrophic muscles suggests that Galgt2 is a therapeutic target with broad potential applications.

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