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• W2125776406 abstract "The lack of functional dystrophin protein in Duchenne muscular dystrophy (DMD) renders muscle fibers highly fragile and susceptible to damage during contractions. Contraction-mediated injury is a major contributor to the progressive degeneration and etiology of muscle wasting in DMD. The prevailing understanding is that large fibers are highly susceptible to contraction damage and are affected preferentially, whereas smaller fibers are relatively spared in DMD. We tested the hypothesis that a pharmacological treatment that caused myofiber hypertrophy would increase the susceptibility of muscles from dystrophin-deficient mdx mice to contraction-induced injury, and thus aggravate the dystrophic pathology. The β-agonist formoterol (100 μg/kg per day, i.p.) was administered to mdx mice for 28 days. Formoterol increased muscle mass, fiber cross-sectional area, and maximum force producing capacity by 30%, 23%, and 21%, respectively, in fast-twitch tibialis anterior muscles of mdx mice. Myofiber hypertrophy and increased maximum force producing capacity were also observed in the predominantly slow-twitch soleus muscles of mdx mice. Our original hypothesis was rejected since tibialis anterior muscles from formoterol-treated mdx mice had lower cumulative force deficits, indicating that they were less susceptible to contraction-induced injury. Formoterol treatment did not affect injury susceptibility in soleus muscles. These findings indicate that making dystrophic muscles bigger protects them from contraction damage and does not aggravate the dystrophic pathophysiology. These novel results further support the contention that anabolic agents have therapeutic potential for muscle wasting conditions including DMD. The lack of functional dystrophin protein in Duchenne muscular dystrophy (DMD) renders muscle fibers highly fragile and susceptible to damage during contractions. Contraction-mediated injury is a major contributor to the progressive degeneration and etiology of muscle wasting in DMD. The prevailing understanding is that large fibers are highly susceptible to contraction damage and are affected preferentially, whereas smaller fibers are relatively spared in DMD. We tested the hypothesis that a pharmacological treatment that caused myofiber hypertrophy would increase the susceptibility of muscles from dystrophin-deficient mdx mice to contraction-induced injury, and thus aggravate the dystrophic pathology. The β-agonist formoterol (100 μg/kg per day, i.p.) was administered to mdx mice for 28 days. Formoterol increased muscle mass, fiber cross-sectional area, and maximum force producing capacity by 30%, 23%, and 21%, respectively, in fast-twitch tibialis anterior muscles of mdx mice. Myofiber hypertrophy and increased maximum force producing capacity were also observed in the predominantly slow-twitch soleus muscles of mdx mice. Our original hypothesis was rejected since tibialis anterior muscles from formoterol-treated mdx mice had lower cumulative force deficits, indicating that they were less susceptible to contraction-induced injury. Formoterol treatment did not affect injury susceptibility in soleus muscles. These findings indicate that making dystrophic muscles bigger protects them from contraction damage and does not aggravate the dystrophic pathophysiology. These novel results further support the contention that anabolic agents have therapeutic potential for muscle wasting conditions including DMD. Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder caused by mutations in the dystrophin gene that result in the complete absence of the membrane-stabilizing protein dystrophin.1Emery AE The muscular dystrophies.Lancet. 2002; 359: 687-695Abstract Full Text Full Text PDF PubMed Scopus (1150) Google Scholar, 2Koenig M Monaco AP Kunkel LM The complete sequence of dystrophin predicts a rod-shaped cytoskeletal protein.Cell. 1988; 53: 219-228Abstract Full Text PDF PubMed Scopus (1276) Google Scholar, 3Sicinski P Geng Y Ryder-Cook AS Barnard EA Darlison MG Barnard PJ The molecular basis of muscular dystrophy in the mdx mouse: a point mutation.Science. 1989; 244: 1578-1580Crossref PubMed Scopus (1003) Google Scholar The loss of this integral muscle protein renders dystrophic muscles fragile and highly susceptible to damage from everyday contractions.4Lynch GS Role of contraction-induced injury in the mechanisms of muscle damage in muscular dystrophy.Clin Exp Pharmacol Physiol. 2004; 31: 557-561Crossref PubMed Scopus (37) Google Scholar, 5Petrof BJ Shrager JB Stedman HH Kelly AM Sweeney HL Dystrophin protects the sarcolemma from stresses developed during muscle contraction.Proc Natl Acad Sci USA. 1993; 90: 3710-3714Crossref PubMed Scopus (1179) Google Scholar What would normally be considered innocuous contractions in healthy muscle causes tears in muscle fibers and a subsequent influx of Ca2+ that activates degenerative pathways in dystrophic muscle.6Blake DJ Weir A Newey SE Davies KE Function and genetics of dystrophin and dystrophin-related proteins in muscle.Physiol Rev. 2002; 82: 291-329Crossref PubMed Scopus (912) Google Scholar Repeated injurious events eventually exhaust the regenerative capacity of dystrophic muscles and infiltration of adipose and connective tissue ensues leading to progressive functional impairments in affected patients.6Blake DJ Weir A Newey SE Davies KE Function and genetics of dystrophin and dystrophin-related proteins in muscle.Physiol Rev. 2002; 82: 291-329Crossref PubMed Scopus (912) Google Scholar Although the most likely cure for DMD will come from gene therapies, either by restoration or replacement of the mutated dystrophin gene, several significant hurdles must be overcome before such treatments become available and accepted.7Lynch GS Ryall JG Role of beta-adrenoceptor signaling in skeletal muscle: implications for muscle wasting and disease.Physiol Rev. 2008; 88: 729-767Crossref PubMed Scopus (294) Google Scholar Until then, alternative therapies are needed that can attenuate the severity and progression of muscle wasting and enhance the quality of life for DMD patients. One of the most widely trialed therapeutic strategies for DMD has been the administration of anabolic agents such as anabolic steroids, myostatin-blocking antibodies/peptides, and β-adrenoceptor agonists (β-agonists).8Bogdanovich S Krag TO Barton ER Morris LD Whittemore LA Ahima RS Khurana TS Functional improvement of dystrophic muscle by myostatin blockade.Nature. 2002; 420: 418-421Crossref PubMed Scopus (721) Google Scholar, 9Fenichel G Pestronk A Florence J Robison V Hemelt V A beneficial effect of oxandrolone in the treatment of Duchenne muscular dystrophy: a pilot study.Neurology. 1997; 48: 1225-1226Crossref PubMed Scopus (47) Google Scholar, 10Skura CL Fowler EG Wetzel GT Graves M Spencer MJ Albuterol increases lean body mass in ambulatory boys with Duchenne or Becker muscular dystrophy.Neurology. 2008; 70: 137-143Crossref PubMed Scopus (44) Google Scholar, 11Fenichel GM Griggs RC Kissel J Kramer TI Mendell JR Moxley RT Pestronk A Sheng K Florence J King WM Pandya S Robison VD Wang H A randomized efficacy and safety trial of oxandrolone in the treatment of Duchenne dystrophy.Neurology. 2001; 56: 1075-1079Crossref PubMed Scopus (77) Google Scholar These approaches have shown improvements in muscle function in some studies,9Fenichel G Pestronk A Florence J Robison V Hemelt V A beneficial effect of oxandrolone in the treatment of Duchenne muscular dystrophy: a pilot study.Neurology. 1997; 48: 1225-1226Crossref PubMed Scopus (47) Google Scholar, 10Skura CL Fowler EG Wetzel GT Graves M Spencer MJ Albuterol increases lean body mass in ambulatory boys with Duchenne or Becker muscular dystrophy.Neurology. 2008; 70: 137-143Crossref PubMed Scopus (44) Google Scholar, 12Harcourt LJ Schertzer JD Ryall JG Lynch GS Low dose formoterol administration improves muscle function in dystrophic mdx mice without increasing fatigue.Neuromuscul Disord. 2007; 17: 47-55Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar but others have shown little or no effect.11Fenichel GM Griggs RC Kissel J Kramer TI Mendell JR Moxley RT Pestronk A Sheng K Florence J King WM Pandya S Robison VD Wang H A randomized efficacy and safety trial of oxandrolone in the treatment of Duchenne dystrophy.Neurology. 2001; 56: 1075-1079Crossref PubMed Scopus (77) Google Scholar Although bigger muscles generally produce more force, it has been suggested that enhancing muscle size in mdx mice would increase their susceptibility to contraction-induced injury.13Deconinck N Dan B Pathophysiology of duchenne muscular dystrophy: current hypotheses.Pediatr Neurol. 2007; 36: 1-7Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar Previous studies have shown that large, fast type II fibers are damaged selectively after lengthening contractions14Lieber RL Friden J Selective damage of fast glycolytic muscle fibres with eccentric contraction of the rabbit tibialis anterior.Acta Physiol Scand. 1988; 133: 587-588Crossref PubMed Scopus (171) Google Scholar, 15Macpherson PC Schork MA Faulkner JA Contraction-induced injury to single fiber segments from fast and slow muscles of rats by single stretches.Am J Physiol. 1996; 271: C1438-C1446PubMed Google Scholar and these fibers are preferentially affected in DMD.16Webster C Silberstein L Hays AP Blau HM Fast muscle fibers are preferentially affected in Duchenne muscular dystrophy.Cell. 1988; 52: 503-513Abstract Full Text PDF PubMed Scopus (452) Google Scholar, 17Petrof BJ Stedman HH Shrager JB Eby J Sweeney HL Kelly AM Adaptations in myosin heavy chain expression and contractile function in dystrophic mouse diaphragm.Am J Physiol. 1993; 265: C834-C841PubMed Google Scholar, 18Childers MK Okamura CS Bogan DJ Bogan JR Petroski GF McDonald K Kornegay JN Eccentric contraction injury in dystrophic canine muscle.Arch Phys Med Rehabil. 2002; 83: 1572-1578Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 19Yuasa K Nakamura A Hijikata T Takeda S Dystrophin deficiency in canine X-linked muscular dystrophy in Japan (CXMDJ) alters myosin heavy chain expression profiles in the diaphragm more markedly than in the tibialis cranialis muscle.BMC Musculoskelet Disord. 2008; 9: 1Crossref PubMed Scopus (21) Google Scholar Conversely, smaller caliber fibers such as those in extraocular and intrinsic laryngeal muscles are spared in DMD patients and animal models of muscular dystrophy.20Khurana TS Prendergast RA Alameddine HS Tome FM Fardeau M Arahata K Sugita H Kunkel LM Absence of extraocular muscle pathology in Duchenne's muscular dystrophy: role for calcium homeostasis in extraocular muscle sparing.J Exp Med. 1995; 182: 467-475Crossref PubMed Scopus (114) Google Scholar, 21Smythe GM Dystrophic pathology in the intrinsic and extrinsic laryngeal muscles in the mdx mouse.J Otolaryngol Head Neck Surg. 2009; 38: 323-336PubMed Google Scholar, 22Kaminski HJ al-Hakim M Leigh RJ Katirji MB Ruff RL Extraocular muscles are spared in advanced Duchenne dystrophy.Ann Neurol. 1992; 32: 586-588Crossref PubMed Scopus (99) Google Scholar, 23Karpati G Carpenter S Small-caliber skeletal muscle fibers do not suffer deleterious consequences of dystrophic gene expression.Am J Med Genet. 1986; 25: 653-658Crossref PubMed Scopus (121) Google Scholar Since contraction-induced injury contributes to the dystrophic pathology, it is imperative that potential therapeutic strategies do not adversely affect the susceptibility of dystrophic muscles to self-injury. Using the well-characterized effect of β-agonists to induce skeletal muscle hypertrophy, we tested the hypothesis that making dystrophic muscles bigger would increase their susceptibility to contraction-mediated injury and thus aggravate the dystrophic pathology. All procedures were approved by the Animal Experimentation Ethics Committee of The University of Melbourne and conformed to the Guidelines for the Care and Use of Experimental Animals described by the National Health and Medical Research Council (Australia). Male C57BL/10ScSn (BL/10) and mdx dystrophic mice (8–10 weeks old; n = 8 per group; 32 total) were obtained from the Animal Resource Centre (Canning Vale, WA, Australia) and housed in the Biological Research Facility at The University of Melbourne under a 12-hour light/dark cycle. The animals were provided access to drinking water and standard chow ad libitum. Mice received daily injections of formoterol (100 μg/kg in saline, i.p.) or an equivalent volume of isotonic saline for 28 days. The methods for measuring contractile function of mouse tibialis anterior (TA) muscles in situ have been described in detail elsewhere.24Schertzer JD Ryall JG Lynch GS Systemic administration of IGF-I enhances oxidative status and reduces contraction-induced injury in skeletal muscles of mdx dystrophic mice.Am J Physiol Endocrinol Metab. 2006; 291: E499-E505Crossref PubMed Scopus (59) Google Scholar Briefly, TA muscles from BL/10 and mdx mice were stimulated by supramaximal 0.2 ms square wave pulses of 350 ms duration, delivered via two wire electrodes adjacent to the peroneal nerve. The contractile properties of the soleus muscle were determined in vitro, as described previously.12Harcourt LJ Schertzer JD Ryall JG Lynch GS Low dose formoterol administration improves muscle function in dystrophic mdx mice without increasing fatigue.Neuromuscul Disord. 2007; 17: 47-55Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar Briefly, soleus muscles were stimulated by supramaximal 0.2 ms square wave pulses of 1200 ms duration, delivered via platinum plate electrodes that flanked the muscle. For both muscles, optimum muscle length (Lo) was determined from maximum isometric twitch force (Pt), and maximum isometric tetanic force (Po) was recorded from the plateau of a complete frequency-force relationship. Specific force (sPo) was determined by normalizing Po to muscle cross-sectional area (CSA) and expressed in kN/m2. The protocol for assessment of contraction-induced injury has been described previously.25Consolino CM Brooks SV Susceptibility to sarcomere injury induced by single stretches of maximally activated muscles of mdx mice.J Appl Physiol. 2004; 96: 633-638Crossref PubMed Scopus (72) Google Scholar, 26Gregorevic P Allen JM Minami E Blankinship MJ Haraguchi M Meuse L Finn E Adams ME Froehner SC Murry CE Chamberlain JS rAAV6-microdystrophin preserves muscle function and extends lifespan in severely dystrophic mice.Nat Med. 2006; 12: 787-789Crossref PubMed Scopus (250) Google Scholar Briefly, muscles were activated maximally and then lengthened at a velocity of two fiber lengths per second (2 Lf/s) at progressively greater magnitudes of stretch (beyond Lf). Maximum isometric force was determined after each lengthening contraction. All muscles were subjected to a 2 minute rest period between successive contractions. Cumulative contraction-induced muscle damage was quantified by determining the force deficit—the difference in Po after each successive lengthening contraction expressed as a percentage of maximum Po before commencing the injury protocol.24Schertzer JD Ryall JG Lynch GS Systemic administration of IGF-I enhances oxidative status and reduces contraction-induced injury in skeletal muscles of mdx dystrophic mice.Am J Physiol Endocrinol Metab. 2006; 291: E499-E505Crossref PubMed Scopus (59) Google Scholar, 25Consolino CM Brooks SV Susceptibility to sarcomere injury induced by single stretches of maximally activated muscles of mdx mice.J Appl Physiol. 2004; 96: 633-638Crossref PubMed Scopus (72) Google Scholar TA and soleus muscles were excised, blotted, and weighed on an analytical balance and then embedded in optimal cutting temperature compound, and frozen in isopentane cooled in liquid nitrogen for later immunohistochemical analyses. Multiple serial sections (5 μm) were thaw-mounted on uncoated, pre-cleaned glass slides. Muscle fiber type-specific oxidative capacity and CSA were estimated from the determination of succinate dehydrogenase activity (SDH) combined with immunolabeling of laminin, myosin heavy-chain I, and myosin heavy-chain IIa in the muscle cross-sections, as described previously.27Koopman R Manders RJ Jonkers RA Hul GB Kuipers H van Loon LJ Intramyocellular lipid and glycogen content are reduced following resistance exercise in untrained healthy males.Eur J Appl Physiol. 2006; 96: 525-534Crossref PubMed Scopus (102) Google Scholar Other sections were stained with Mayer's hematoxylin and eosin to visualize general muscle architecture. Digital images of stained sections (four images per muscle section) were obtained using an upright microscope (×20 objective) with camera (Axio Imager D1, Carl Zeiss, Wrek Göttingen, Germany), controlled by AxioVision AC software (AxioVision AC Rel. 4.7.1, Carl Zeiss Imaging Solutions, Wrek, Göttingen, Germany). Images were quantified using AxioVision 4.7.1 software for average fiber CSA, fiber type, and SDH activity as described previously.27Koopman R Manders RJ Jonkers RA Hul GB Kuipers H van Loon LJ Intramyocellular lipid and glycogen content are reduced following resistance exercise in untrained healthy males.Eur J Appl Physiol. 2006; 96: 525-534Crossref PubMed Scopus (102) Google Scholar In brief, the signal derived from the antibody against laminin was used to select single muscle fibers. Antibodies against myosin heavy-chains I and IIa, were used to differentiate between fiber types. Since the TA muscles consisted of only negligible numbers of type I muscle fibers, these were not used in the analysis. Approximately 360 muscle fibers were quantified in each section. The minimal Feret's diameter is the minimum distance between opposing parallel tangents of a muscle fiber. Dystrophic muscles display a high degree of variability in the myofiber size, which can be quantified as the minimal Feret's variance coefficient. This parameter is highly sensitive and is used routinely for detecting differences between dystrophic and healthy muscles.28Briguet A Courdier-Fruh I Foster M Meier T Magyar JP Histological parameters for the quantitative assessment of muscular dystrophy in the mdx-mouse.Neuromuscul Disord. 2004; 14: 675-682Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar All values are expressed as mean ± SEM unless specified otherwise. Groups were compared using one-way analysis of variance (analysis of variance) where appropriate. Bonferroni's post hoc multiple comparison procedure was used to determine significant differences between groups. The level of significance was set at P < 0.05 for all comparisons. Consistent with the results of our previous investigations on the effect of β-agonists on skeletal muscles, formoterol treatment increased muscle mass in BL/10 and mdx mice by 22% and 30%, respectively (P < 0.05, Figure 1A). Maximal Po was increased by 19% and 21% in formoterol treated BL/10 and mdx mice, respectively (P < 0.05, Figure 1B). Specific (normalized) force (sPo) was higher in muscles from BL/10 mice, as compared with mdx mice (P < 0.05, Figure 1C), but formoterol treatment did not affect sPo in either strain. Muscles from BL/10 mice were less susceptible to contraction-induced damage than those from mdx mice (P < 0.05, Figure 1D). Formoterol treatment significantly reduced the susceptibility to contraction-induced damage in muscles from mdx mice as evidenced by lower cumulative force deficits from the 10% stretch onwards in the injury protocol (P < 0.05, Figure 1D). Muscles from BL/10 mice displayed small, but significant, force deficits of 10% to 15% after the contraction-induced injury protocol. Representative H&E-stained sections and CSA data for the TA muscle are presented in Figures 2, A and B. The mean CSA of myofibers from TA muscles of formoterol-treated mdx mice was 23% greater than in muscle from untreated mdx mice (P < 0.05, Figure 2B). SDH staining intensity, an indirect measure of oxidative capacity, was 36% lower in muscles from mdx than BL/10 mice (P < 0.05, Figure 2C). Formoterol did not affect SDH staining intensity or fiber type composition (data not shown). Minimal Feret's variance was significantly lower in muscles from BL/10, as compared with mdx mice (P < 0.05). Formoterol treatment had no effect on this measure of the dystrophic pathology (315 ± 7 vs. 300 ± 8 in mdx control and formoterol treated, respectively). Soleus muscle mass was increased by 29% in formoterol-treated mdx mice (P < 0.05, Figure 3A). In BL/10 mice the difference in soleus muscle mass after treatment (16%) was of borderline significance (P = 0.053, t-test). Formoterol treatment increased maximal Po in soleus muscles of BL/10 and mdx mice by 15% and 11%, respectively (P < 0.05, Figure 3B,C). Susceptibility to contraction-induced injury was neither different between soleus muscles of BL/10 and mdx mice, nor different within strains after formoterol treatment, as evidenced by the similar cumulative force deficits after each magnitude of strain (Figure 3D). Formoterol treatment did not alter fiber type composition in the soleus muscles of BL/10 or mdx mice (data not shown). Minimal Feret's variance28Briguet A Courdier-Fruh I Foster M Meier T Magyar JP Histological parameters for the quantitative assessment of muscular dystrophy in the mdx-mouse.Neuromuscul Disord. 2004; 14: 675-682Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar was significantly lower in soleus muscles of BL/10 compared with mdx mice (P < 0.05). Formoterol treatment had no effect on this measure of the dystrophic pathology (260 ± 6 vs. 253 ± 6 for untreated and formoterol treated mdx mice, respectively). The most important finding of this study was that larger dystrophic skeletal muscles after treatment with the β-agonist, formoterol, were protected from contraction-mediated damage. Based on the prevailing knowledge that smaller caliber muscle fibers were protected in muscular dystrophy, we originally proposed that hypertrophied muscles would be more susceptible to injury and that this would aggravate the dystrophic pathology. In contrast, despite formoterol treatment increasing muscle mass and force production, the cumulative force deficit was actually lower in TA muscles of treated than untreated mdx mice. The findings support the contention that enhancing muscle size confers protection to fast-twitch dystrophic muscles and thus anabolic agents have therapeutic potential for skeletal muscle diseases. In DMD, the absence of dystrophin renders muscles highly susceptible to contraction-induced injury.29Lynch GS Rafael JA Chamberlain JS Faulkner JA Contraction-induced injury to single permeabilized muscle fibers from mdx, transgenic mdx, and control mice.Am J Physiol Cell Physiol. 2000; 279: C1290-C1294PubMed Google Scholar This injury contributes to the etiology of the dystrophic pathology, ultimately leading to a loss of functional tissue. As a consequence, the extra workload imposed on the fewer remaining functional muscle fibers causes them to hypertrophy and be more vulnerable to contraction-mediated damage.25Consolino CM Brooks SV Susceptibility to sarcomere injury induced by single stretches of maximally activated muscles of mdx mice.J Appl Physiol. 2004; 96: 633-638Crossref PubMed Scopus (72) Google Scholar, 30Zammit PS Partridge TA Sizing up muscular dystrophy.Nat Med. 2002; 8: 1355-1356Crossref PubMed Scopus (18) Google Scholar Pharmacological approaches that cause muscle fiber hypertrophy have been suggested as being detrimental for muscular dystrophy if they aggravated the pathology. For example, anabolic steroids were shown in one study to have beneficial effects on muscle strength but exacerbated the dystrophic pathology.31Krahn MJ Anderson JE Anabolic steroid treatment increases myofiber damage in mdx mouse muscular dystrophy.J Neurol Sci. 1994; 125: 138-146Abstract Full Text PDF PubMed Scopus (21) Google Scholar These seemingly contradictory results can be reconciled with an understanding that although bigger myofibers might produce more force, they might also be more easily damaged by their own contractions. Previous studies from our laboratory have demonstrated that formoterol can increase muscle mass and muscle fiber CSA in rats and mice.12Harcourt LJ Schertzer JD Ryall JG Lynch GS Low dose formoterol administration improves muscle function in dystrophic mdx mice without increasing fatigue.Neuromuscul Disord. 2007; 17: 47-55Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 32Ryall JG Sillence MN Lynch GS Systemic administration of beta2-adrenoceptor agonists, formoterol and salmeterol, elicit skeletal muscle hypertrophy in rats at micromolar doses.Br J Pharmacol. 2006; 147: 587-595Crossref PubMed Scopus (86) Google Scholar Similarly, in the present study, formoterol treatment increased muscle mass in BL/10 and mdx mice. Formoterol treatment did not affect oxidative capacity in either mdx or BL/10 mice. However, muscle fiber CSA was significantly greater in formoterol-treated mice, which was mediated primarily by hypertrophy of type IIb fibers, with no change in mean CSA of type IIa fibers. The absence of changes in fiber type and oxidative capacity indicate that the hypertrophic response of type IIb fibers to formoterol treatment was the major factor responsible for conferring protection from contraction-induced injury. These findings have major implications for DMD patients since large type IIb fibers bear considerable loads, and so preventing their loss and/or improving their contractile protein content could help preserve mobility and quality of life in affected patients.16Webster C Silberstein L Hays AP Blau HM Fast muscle fibers are preferentially affected in Duchenne muscular dystrophy.Cell. 1988; 52: 503-513Abstract Full Text PDF PubMed Scopus (452) Google Scholar Since hypertrophy of the type IIb fibers was the major factor protecting the TA muscle from contraction-induced injury in formoterol treated mdx mice, we also examined the susceptibility to contraction-induced damage in a muscle with a highly oxidative phenotype. Interestingly, we found no difference in the susceptibility to contraction-induced damage in soleus muscles from mdx compared with control mice. The high degree of resistance to injury in soleus muscles from lengthening contractions has been demonstrated elsewhere,25Consolino CM Brooks SV Susceptibility to sarcomere injury induced by single stretches of maximally activated muscles of mdx mice.J Appl Physiol. 2004; 96: 633-638Crossref PubMed Scopus (72) Google Scholar, 33Gehrig SM Ryall JG Schertzer JD Lynch GS Insulin-like growth factor-I analogue protects muscles of dystrophic mdx mice from contraction-mediated damage.Exp Physiol. 2008; 93: 1190-1198Crossref PubMed Scopus (34) Google Scholar but the mechanisms for protection are not well understood. It is reasonable to suggest that the obvious difference in fiber types within TA and soleus muscles would explain the differences in their relative pathology and susceptibility to injury. In the present study, the TA muscles in mdx mice were comprised of >90% of type IIb fibers, while the soleus muscle had fewer than 10% type II fibers. These differences in fiber type proportions may also contribute to the lack of substantial fiber hypertrophy in the soleus muscles. Taken together, our findings revealed that β-agonist-induced hypertrophy conferred protection to fast-twitch dystrophic muscles from contraction-induced injury and therefore remains a valid and important therapeutic approach for the treatment of muscular dystrophies." @default.
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• W2125776406 title "Making Fast-Twitch Dystrophic Muscles Bigger Protects Them from Contraction Injury and Attenuates the Dystrophic Pathology" @default.
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