Treadmill running causes significant fiber damage in skeletal muscle of KATP channel-deficient mice

Although it has been suggested that the ATP-sensitive K+ (KATP) channel protects muscle against function impairment, most studies have so far given little evidence for significant perturbation in the integrity and function of skeletal muscle fibers from inactive mice that lack KATP channel activity in their cell membrane. The objective was, therefore, to test the hypothesis that KATP channel-deficient skeletal muscle fibers become damaged when mice are subjected to stress. Wild-type and KATP channel-deficient mice (Kir6.2−/− mice) were subjected to 4–5 wk of treadmill running at either 20 m/min with 0° inclination or at 24 m/min with 20° uphill inclination. Muscles of all wild-type mice and of nonexercised Kir6.2−/− mice had very few fibers with internal nuclei. After 4–5 wk of treadmill running, there was little evidence for connective tissues and mononucleated cells in Kir6.2−/− hindlimb muscles, whereas the number of fibers with internal nuclei, which appear when damaged fibers are regenerated by satellite cells, was significantly higher in Kir6.2−/− than wild-type mice. Between 5% and 25% of the total number of fibers in Kir6.2−/− extensor digitum longus, plantaris, and tibialis muscles had internal nuclei, and most of such fibers were type IIB fibers. Contrary to hindlimb muscles, diaphragms of Kir6.2−/− mice that had run at 24 m/min had few fibers with internal nuclei, but mild to severe fiber damage was observed. In conclusion, the study provides for the first time evidence 1) that the KATP channels of skeletal muscle are essential to prevent fiber damage, and thus muscle dysfunction; and 2) that the extent of fiber damage is greater and the capacity of fiber regeneration is less in Kir6.2−/− diaphragm muscles compared with hindlimb muscles.

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Exercise-induced alterations and loss of sarcomeric M-line organization in the diaphragm muscle of obscurin knockout mice

AJP Cell Physiology ◽

10.1152/ajpcell.00098.2016 ◽

2017 ◽

Vol 312 (1) ◽

pp. C16-C28 ◽

Cited By ~ 13

Author(s):

D. Randazzo ◽

B. Blaauw ◽

C. Paolini ◽

E. Pierantozzi ◽

S. Spinozzi ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Fibers ◽

Detailed Examination ◽

Diaphragm Muscle ◽

Hindlimb Muscles ◽

Skeletal Muscle Fibers ◽

Exercise Induced ◽

Old Mice ◽

Ankyrin B ◽

Deficient Mice

We recently reported that skeletal muscle fibers of obscurin knockout (KO) mice present altered distribution of ankyrin B (ankB), disorganization of the subsarcolemmal microtubules, and reduced localization of dystrophin at costameres. In addition, these mice have impaired running endurance and increased exercise-induced sarcolemmal damage compared with wild-type animals. Here, we report results from a combined approach of physiological, morphological, and structural studies in which we further characterize the skeletal muscles of obscurin KO mice. A detailed examination of exercise performance, using different running protocols, revealed that the reduced endurance of obscurin KO animals on the treadmill depends on exercise intensity and age. Indeed, a mild running protocol did not evidence significant differences between control and obscurin KO mice, whereas comparison of running abilities of 2-, 6-, and 11-mo-old mice exercised at exhaustion revealed a progressive age-dependent reduction of the exercise tolerance in KO mice. Histological analysis indicated that heavy exercise induced leukocyte infiltration, fibrotic connective tissue deposition, and hypercontractures in the diaphragm of KO mice. On the same line, electron microscopy revealed that, in the diaphragm of exercised obscurin KO mice, but not in the hindlimb muscles, both M-line and H-zone of sarcomeres appeared wavy and less defined. Altogether, these results suggest that obscurin is required for the maintenance of morphological and ultrastructural integrity of skeletal muscle fibers against damage induced by intense mechanical stress and point to the diaphragm as the skeletal muscle most severely affected in obscurin-deficient mice.

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The ROS scavenger PDTC affects adaptation to treadmill running in mice: distinct effects on murine body mass, resting heart rate and skeletal muscle fiber type composition

Journal of Experimental Biology ◽

10.1242/jeb.234237 ◽

2021 ◽

Vol 224 (6) ◽

pp. jeb234237

Author(s):

Franziska Röchner ◽

Angelika Schmitt ◽

Anne-Lena Brändle ◽

Annunziata Fragasso ◽

Barbara Munz

Keyword(s):

Skeletal Muscle ◽

Heart Rate ◽

Muscle Hypertrophy ◽

Muscle Fibers ◽

Treadmill Running ◽

Moderate Intensity ◽

Resting Heart Rate ◽

Skeletal Muscle Hypertrophy ◽

Skeletal Muscle Fibers ◽

Ros Scavenger

ABSTRACTRegular exercise induces a broad spectrum of adaptation reactions in a variety of tissues and organs. However, the respective mechanisms are incompletely understood. In the context of their analysis, animal model systems, specifically rodent treadmill running protocols, play an important role. However, few researchers have studied different aspects of adaptation, such as cardiorespiratory and skeletal muscle training effects, within one set of experiments. Here, we analyzed physiological adaptation to 10 weeks of regular, moderate-intensity, uphill treadmill running in mice, a widely used model for endurance exercise training. To study the effects of reactive oxygen species (ROS), which have been suggested to be major regulators of training adaptation, a subgroup of mice was treated with the ROS scavenger PDTC (pyrrolidine dithiocarbamate). We found that mass gain in mice that exercised under PDTC treatment lagged behind that of all other experimental groups. In addition, both exercise and PDTC significantly and additively decreased resting heart rate. Furthermore, there was a trend towards an enhanced proportion of type 2A skeletal muscle fibers and differential expression of metabolism-associated genes, indicating metabolic and functional adaptation of skeletal muscle fibers. By contrast, there were no effects on grip strength and relative mass of individual muscles, suggesting that our protocol of uphill running did not increase skeletal muscle hypertrophy and strength. Taken together, our data suggest that a standard protocol of moderate-intensity uphill running induces adaptation reactions at multiple levels, part of which might be modulated by ROS, but does not enhance skeletal muscle hypertrophy and force.

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Exercise Can Reverse the Phenotype of Biglycan Deficient Mice

Advances in Bioengineering ◽

10.1115/imece2003-43116 ◽

2003 ◽

Cited By ~ 1

Author(s):

Joseph M. Wallace ◽

Rupak M. Rajachar ◽

Xiao-Dong Chen ◽

Songtao Shi ◽

Matthew R. Allen ◽

...

Keyword(s):

Skeletal Development ◽

Skeletal Growth ◽

Treadmill Running ◽

Wild Type ◽

Connective Tissues ◽

Cross Sectional ◽

Age Dependent ◽

Skeletal Phenotype ◽

Deficient Mice ◽

Wild Type Control

Biglycan (Bgn) is a small leucine-rich proteoglycan (SLRP) that is enriched in bone and other skeletal connective tissues and is responsible, in part, for the regulation of postnatal skeletal growth (Bianco, 1990). Mice lacking Bgn display reduced skeletal development and a lower peak bone mass that leads to age-dependent osteopenia (Xu, 1998). We hypothesized that mechanical loading could reverse the skeletal phenotype of Bgn knockout mice. To test this hypothesis, we determined the effects of treadmill running on the geometric, mechanical and mineral properties of Bgn deficient mice bones. After sacrifice, femora and tibiae were tested in 4 point bending and cross-sectional geometric properties and bone mineral parameters were measured. Exercise was able to partially reverse the skeletal phenotype of the Bgn knockouts by increasing both the geometric and mechanical properties of the tibiae to values equal to or greater than those of wild type control mice.

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Rapid Changes in Mitochondrial Ca2+-Concentration in Fast Skeletal Muscle Fibers from Wild Type and Calsequestrin Null Mice

Biophysical Journal ◽

10.1016/j.bpj.2011.11.1719 ◽

2012 ◽

Vol 102 (3) ◽

pp. 312a

Author(s):

Michele Scorzeto ◽

Marta Giacomello ◽

Luana Toniolo ◽

Marta Canato ◽

Cecilia Paolini ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Fibers ◽

Wild Type ◽

Fast Skeletal Muscle ◽

Skeletal Muscle Fibers ◽

Rapid Changes

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An investigation of p53 in skeletal muscle aging

Journal of Applied Physiology ◽

10.1152/japplphysiol.00363.2019 ◽

2019 ◽

Vol 127 (4) ◽

pp. 1075-1084 ◽

Cited By ~ 2

Author(s):

Scott M. Ebert ◽

Jason M. Dierdorff ◽

David K. Meyerholz ◽

Steven A. Bullard ◽

Asma Al-Zougbi ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Muscle Fibers ◽

Skeletal Muscle Atrophy ◽

P53 Expression ◽

Skeletal Muscle Fibers ◽

Age Related ◽

Skeletal Muscle Aging ◽

And Function

Age-related skeletal muscle atrophy is a very common and serious condition that remains poorly understood at the molecular level. Several lines of evidence have suggested that the tumor suppressor p53 may play a central, causative role in skeletal muscle aging, whereas other, apparently contradictory lines of evidence have suggested that p53 may be critical for normal skeletal muscle function. To help address these issues, we performed an aging study in male muscle-specific p53-knockout mice (p53 mKO mice), which have a lifelong absence of p53 expression in skeletal muscle fibers. We found that the absence of p53 expression in skeletal muscle fibers had no apparent deleterious or beneficial effects on skeletal muscle mass or function under basal conditions up to 6 mo of age, when mice are fully grown and exhibit peak muscle mass and function. Furthermore, at 22 and 25 mo of age, when age-related muscle weakness and atrophy are clearly evident in mice, p53 mKO mice demonstrated no improvement or worsening of skeletal muscle mass or function relative to littermate control mice. At advanced ages, p53 mKO mice began to die prematurely and had an increased incidence of osteosarcoma, precluding analyses of muscle mass and function in very old p53 mKO mice. In light of these results, we conclude that p53 expression in skeletal muscle fibers has minimal if any direct, cell autonomous effect on basal or age-related changes in skeletal muscle mass and function up to at least 22 mo of age. NEW & NOTEWORTHY Previous studies implicated the transcriptional regulator p53 as a potential mediator of age-related skeletal muscle weakness and atrophy. We tested this hypothesis by investigating the effect of aging in muscle-specific p53-knockout mice. Our results strongly suggest that p53 activity within skeletal muscle fibers is not required for age-related skeletal muscle atrophy or weakness.

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Type 2X-myosin heavy chain is coded by a muscle fiber type-specific and developmentally regulated gene.

The Journal of Cell Biology ◽

10.1083/jcb.123.4.823 ◽

1993 ◽

Vol 123 (4) ◽

pp. 823-835 ◽

Cited By ~ 135

Author(s):

C DeNardi ◽

S Ausoni ◽

P Moretti ◽

L Gorza ◽

M Velleca ◽

...

Keyword(s):

Skeletal Muscle ◽

Myosin Heavy Chain ◽

Heavy Chain ◽

Muscle Development ◽

Fiber Type ◽

Muscle Fibers ◽

Hindlimb Muscles ◽

Isolation And Characterization ◽

Skeletal Muscle Fibers ◽

Myhc Isoforms

We have previously reported the identification of a distinct myosin heavy chain (MyHC) isoform in a major subpopulation of rat skeletal muscle fibers, referred to as 2X fibers (Schiaffino, S., L. Gorza, S. Sartore, L. Saggin, M. Vianello, K. Gundersen, and T. Lømo. 1989. J. Muscle Res. Cell Motil. 10:197-205). However, it was not known whether 2X-MyHC is the product of posttranslational modification of other MyHCs or is coded by a distinct mRNA. We report here the isolation and characterization of cDNAs coding a MyHC isoform that is expressed in type 2X skeletal muscle fibers. 2X-MyHC transcripts differ from other MyHC transcripts in their restriction map and 3' end sequence and are thus derived from a distinct gene. In situ hybridization analyses show that 2X-MyHC transcripts are expressed at high levels in the diaphragm and fast hindlimb muscles and can be coexpressed either with 2B- or 2A-MyHC transcripts in a number of fibers. At the single fiber level the distribution of each MyHC mRNA closely matches that of the corresponding protein, determined by specific antibodies on serial sections. In hindlimb muscles 2X-, 2A-, and 2B-MyHC transcripts are first detected by postnatal day 2-5 and display from the earliest stages a distinct pattern of distribution in different muscles and different fibers. The emergence of type 2 MyHC isoforms thus defines a distinct neonatal phase of fiber type differentiation during muscle development. The functional significance of MyHC isoforms is discussed with particular reference to the velocity of shortening of skeletal muscle fibers.

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