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      Eccentric contractions disrupt FKBP12 content in mouse skeletal muscle

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          Abstract

          Strength deficits associated with eccentric contraction‐induced muscle injury stem, in part, from impaired voltage‐gated sarcoplasmic reticulum (SR) Ca 2+ release. FKBP12 is a 12‐kD immunophilin known to bind to the SR Ca 2+ release channel (ryanodine receptor, RyR1) and plays an important role in excitation‐contraction coupling. To assess the effects of eccentric contractions on FKBP12 content, we measured anterior crural muscle (tibialis anterior [TA], extensor digitorum longus [EDL], extensor hallucis longus muscles) strength and FKBP12 content in pellet and supernatant fractions after centrifugation via immunoblotting from mice before and after a single bout of either 150 eccentric or concentric contractions. There were no changes in peak isometric torque or FKBP12 content in TA muscles after concentric contractions. However, FKBP12 content was reduced in the pelleted fraction immediately after eccentric contractions, and increased in the soluble protein fraction 3 day after injury induction. FKBP12 content was correlated ( P = 0.025; R 2= 0.38) to strength deficits immediately after injury induction. In summary, eccentric contraction‐induced muscle injury is associated with significant alterations in FKBP12 content after injury, and is correlated with changes in peak isometric torque.

          Abstract

          Eccentric contraction‐induced muscle injury is associated with immediate and prolonged strength deficits that stem in part from impaired sarcoplasmic reticulum (SR) calcium release. The content of FKBP12, a 12‐kD immunophilin known to bind to the SR calcium release channel and influence SR calcium release, is reduced in mouse skeletal muscle immediately after injury induction and is significantly associated with strength deficits.

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          Exercise-induced muscle damage in humans.

          Monica J Hubal, John Clarkson (2002)
          Exercise-induced muscle injury in humans frequently occurs after unaccustomed exercise, particularly if the exercise involves a large amount of eccentric (muscle lengthening) contractions. Direct measures of exercise-induced muscle damage include cellular and subcellular disturbances, particularly Z-line streaming. Several indirectly assessed markers of muscle damage after exercise include increases in T2 signal intensity via magnetic resonance imaging techniques, prolonged decreases in force production measured during both voluntary and electrically stimulated contractions (particularly at low stimulation frequencies), increases in inflammatory markers both within the injured muscle and in the blood, increased appearance of muscle proteins in the blood, and muscular soreness. Although the exact mechanisms to explain these changes have not been delineated, the initial injury is ascribed to mechanical disruption of the fiber, and subsequent damage is linked to inflammatory processes and to changes in excitation-contraction coupling within the muscle. Performance of one bout of eccentric exercise induces an adaptation such that the muscle is less vulnerable to a subsequent bout of eccentric exercise. Although several theories have been proposed to explain this "repeated bout effect," including altered motor unit recruitment, an increase in sarcomeres in series, a blunted inflammatory response, and a reduction in stress-susceptible fibers, there is no general agreement as to its cause. In addition, there is controversy concerning the presence of sex differences in the response of muscle to damage-inducing exercise. In contrast to the animal literature, which clearly shows that females experience less damage than males, research using human studies suggests that there is either no difference between men and women or that women are more prone to exercise-induced muscle damage than are men.
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            Remodeling of ryanodine receptor complex causes "leaky" channels: a molecular mechanism for decreased exercise capacity.

            Steven R. Reiken, Stephan Lehnart, Chuan-xian Deng … (2008)
            During exercise, defects in calcium (Ca2+) release have been proposed to impair muscle function. Here, we show that during exercise in mice and humans, the major Ca2+ release channel required for excitation-contraction coupling (ECC) in skeletal muscle, the ryanodine receptor (RyR1), is progressively PKA-hyperphosphorylated, S-nitrosylated, and depleted of the phosphodiesterase PDE4D3 and the RyR1 stabilizing subunit calstabin1 (FKBP12), resulting in "leaky" channels that cause decreased exercise tolerance in mice. Mice with skeletal muscle-specific calstabin1 deletion or PDE4D deficiency exhibited significantly impaired exercise capacity. A small molecule (S107) that prevents depletion of calstabin1 from the RyR1 complex improved force generation and exercise capacity, reduced Ca2+-dependent neutral protease calpain activity and plasma creatine kinase levels. Taken together, these data suggest a possible mechanism by which Ca2+ leak via calstabin1-depleted RyR1 channels leads to defective Ca2+ signaling, muscle damage, and impaired exercise capacity.
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              Ca2+-dependent proteolysis of junctophilin-1 and junctophilin-2 in skeletal and cardiac muscle.

              Damon G. Lamb, T L Dutka, Sydney Murphy … (2013)
              Excessive increases in intracellular [Ca(2+)] in skeletal muscle fibres cause failure of excitation-contraction coupling by disrupting communication between the dihydropyridine receptors in the transverse tubular system and the Ca(2+) release channels (RyRs) in the sarcoplasmic reticulum (SR), but the exact mechanism is unknown. Previous work suggested a possible role of Ca(2+)-dependent proteolysis in this uncoupling process but found no proteolysis of the dihydropyridine receptors, RyRs or triadin. Junctophilin-1 (JP1; ∼90 kDa) stabilizes close apposition of the transverse tubular system and SR membranes in adult skeletal muscle; its C-terminal end is embedded in the SR and its N-terminal associates with the transverse tubular system membrane. Exposure of skeletal muscle homogenates to precisely set [Ca(2+)] revealed that JP1 undergoes Ca(2+)-dependent proteolysis over the physiological [Ca(2+)] range in tandem with autolytic activation of endogenous μ-calpain. Cleavage of JP1 occurs close to the C-terminal, yielding a ∼75 kDa diffusible fragment and a fixed ∼15 kDa fragment. Depolarization-induced force responses in rat skinned fibres were abolished following 1 min exposure to 40 μm Ca(2+), with accompanying loss of full-length JP1. Supraphysiological stimulation of rat skeletal muscle in vitro by repeated tetanic stimulation in 30 mm caffeine also produced marked proteolysis of JP1 (and not RyR1). In dystrophic mdx mice, JP1 proteolysis is seen in limb muscles at 4 and not at 10 weeks of age. Junctophilin-2 in cardiac and skeletal muscle also undergoes Ca(2+)-dependent proteolysis, and junctophilin-2 levels are reduced following cardiac ischaemia-reperfusion. Junctophilin proteolysis may contribute to skeletal muscle weakness and cardiac dysfunction in a range of circumstances.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Physiol Rep
                Journal ID (iso-abbrev): Physiol Rep
                Journal ID (hwp): physreports
                Journal ID (publisher-id): phy2
                Title: Physiological Reports
                Publisher: Wiley Periodicals, Inc.
                ISSN (Electronic): 2051-817X
                Publication date Collection: 1 July 2014
                Publication date (Electronic): 17 July 2014
                Volume: 2
                Issue: 7
                Electronic Location Identifier: e12081
                Affiliations
                [1 ]Department of Kinesiology and Health, Muscle Biology Laboratory, Georgia State University, Atlanta, 30302, Georgia
                Author notes
                Correspondence: Christopher P. Ingalls, Department of Kinesiology and Health, Georgia State University, Atlanta, GA 30302‐3975. Tel: (404)‐413‐8377 Fax: (404)‐413‐8053 E‐mail: cingalls@ 123456gsu.edu
                Article
                Publisher ID: phy212081
                DOI: 10.14814/phy2.12081
                PMC ID: 4187567
                PubMed ID: 25347864
                SO-VID: 7fad913a-aba2-49d4-9db9-535738c42c84
                Copyright © © 2014 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.
                License:

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 13 March 2014
                Date revision received : 13 June 2014
                Date accepted : 13 June 2014
                Categories
                Subject: Original Research

                Keywords: damage,force,mouse,recovery,skeletal muscle
                Data availability:
                Keywords: damage, force, mouse, recovery, skeletal muscle

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