Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Feb 1;126(2):363-375.
doi: 10.1152/japplphysiol.00948.2018. Epub 2018 Dec 20.

Isometric Resistance Training Increases Strength and Alters Histopathology of Dystrophin-Deficient Mouse Skeletal Muscle

Affiliations
Free PMC article

Isometric Resistance Training Increases Strength and Alters Histopathology of Dystrophin-Deficient Mouse Skeletal Muscle

Angus Lindsay et al. J Appl Physiol (1985). .
Free PMC article

Abstract

Mutation to the dystrophin gene causes skeletal muscle weakness in patients with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD). Deliberation continues regarding implications of prescribing exercise for these patients. The purpose of this study was to determine whether isometric resistance exercise (~10 tetanic contractions/session) improves skeletal muscle strength and histopathology in the mdx mouse model of DMD. Three isometric training sessions increased in vivo isometric torque (22%) and contractility rates (54%) of anterior crural muscles of mdx mice. Mice expressing a BMD-causing missense mutated dystrophin on the mdx background showed comparable increases in torque (22%), while wild-type mice showed less change (11%). Increases in muscle function occurred within 1 h and peaked 3 days posttraining; however, the adaptation was lost after 7 days unless retrained. Six isometric training sessions over 4 wk caused increased isometric torque (28%) and contractility rates (22-28%), reduced fibrosis, as well as greater uniformity of fiber cross-sectional areas, fewer embryonic myosin heavy-chain-positive fibers, and more satellite cells in tibialis anterior muscle compared with the contralateral untrained muscle. Ex vivo functional analysis of isolated extensor digitorum longus (EDL) muscle from the trained hindlimb revealed greater absolute isometric force, lower passive stiffness, and a lower susceptibility to eccentric contraction-induced force loss compared with untrained EDL muscle. Overall, these data support the concept that exercise training in the form of isometric tetanic contractions can improve contractile function of dystrophin-deficient muscle, indicating a potential role for enhancing muscle strength in patients with DMD and BMD. NEW & NOTEWORTHY We focused on adaptive responses of dystrophin-deficient mouse skeletal muscle to isometric contraction training and report that in the absence of dystrophin (or in the presence of a mutated dystrophin), strength and muscle histopathology are improved. Results suggest that the strength gains are associated with fiber hypertrophy, reduced fibrosis, increased number of satellite cells, and blunted eccentric contraction-induced force loss in vitro. Importantly, there was no indication that the isometric exercise training was deleterious to dystrophin-deficient muscle.

Keywords: Becker muscular dystrophy; Duchenne muscular dystrophy; exercise; satellite cells; skeletal muscle.

Conflict of interest statement

No conflicts of interest, financial or otherwise, are declared by the authors.

Figures

Fig. 1.
Fig. 1.
Three sessions of isometric strength training increased anterior hindlimb muscle torque and contractility of mdx mice in vivo. Peak isometric torque (A), peak isometric torque normalized by body mass (B), maximal tetanic rates of contraction (C), and maximal rates of tetanic relaxation (D) in C57BL/10 (n = 10) and mdx (n = 15) mice. *Significantly different from training session 1 within genotype, A–C: P < 0.001; D: P < 0.013.
Fig. 2.
Fig. 2.
Torque-frequency relationships for C57BL/10 and mdx mice following three sessions of isometric strength training. Isometric torque as a percentage of maximum for C57BL/10 (n = 10; A) and mdx (n = 15; B) mice. Absolute torque for C57BL/10 (C) and mdx (D) mice. *Significantly different from training session 1, A, B, and D: P < 0.05; C: P < 0.010.
Fig. 3.
Fig. 3.
Recovery of isometric torque 1 day to 10 days following a series of eccentric contractions. Recovery of isometric torque (A) and number of eccentric contractions (A, inset) to reach 50% torque loss in C57BL/10 mice (n = 10). Recovery of isometric torque (B) and number of eccentric contractions (B, inset) to reach 70% torque loss and in mdx mice (n = 15). *Significantly different from untrained, A: P < 0.001; B: P = 0.001.
Fig. 4.
Fig. 4.
A single isometric strength training session elicits an immediate increase in torque. Isometric torque (A), maximal tetanic rate of contraction (B), and maximal rate of relaxation (C) following a single isometric training session. Each time point represents a separate group of mice (n ≥ 8/group) trained once and retested at the specified time post-training. *Significantly different from 1 day, P < 0.05. #Significantly different from 3 days, P < 0.05. $Significantly different from all other time points, P < 0.05.
Fig. 5.
Fig. 5.
Isometric strength training increases in vivo isometric torque and muscle contractility in mL172H [expresses a Becker muscular dystrophy (BMD) mutated skeletal muscle-specific dystrophin; n = 8] but not Dys∆R4–23/∆CT-mdx mice (expresses a skeletal muscle-specific microdystrophin; n = 7). Isometric torque (A and B), maximal rates of contraction (C and D), and maximal rates of relaxation (E and F) following three isometric training sessions. *Significantly different from training session 1, A: P = 0.010; C and E: P < 0.001; D: P = 0.043.
Fig. 6.
Fig. 6.
Six isometric training sessions of the anterior hindlimb muscles over 4-wk increases and maintains in vivo isometric torque and muscle contractility of mdx mice (n = 15). Isometric torque (A), specific isometric torque (B), maximal tetanic rate of contraction (C), maximal rate of tetanic relaxation (D), absolute torque frequency (E), isometric torque as a percentage of maximum (F), and frequency required to generate 50% max torque (frequency 50) (G) following six sessions of isometric strength training. *Significantly different from training session 1, A C, D, and G: P < 0.001; B: P = 0.005. Statistical significance is not presented on graphs E and F for simplicity.
Fig. 7.
Fig. 7.
Six isometric training sessions over 4 wk reduces passive torque and lowers fibrosis of the anterior hindlimb muscles about the ankle of mdx mice. A: passive torque of the anterior hindlimb muscles about the ankle (n = 15). *Significantly different from training session 1, P < 0.001. Representative images of Sirius red/fast green stain for collagen from untrained and trained tibialis anterior (TA) muscles (B) and quantification of collagen staining (n = 5; C). *Significantly different from untrained, C: P = 0.021.
Fig. 8.
Fig. 8.
Six isometric training sessions over 4-wk shifts the distribution of fiber size in tibialis anterior (TA) muscle fibers of mdx mice (n = 5). Representative images of hematoxylin-and-eosin (H&E)-stained fibers from untrained and trained TA muscles (A), cross-sectional area (CSA) of muscle fibers from untrained and trained TA muscle (B), and centrally nucleated muscle fibers (C) from untrained and trained TA muscle.
Fig. 9.
Fig. 9.
Six isometric training sessions over 4 wk results in fewer embryonic myosin heavy chain (eMHC) positive fibers in the tibialis anterior (TA) muscle of mdx mice (n = 5). Representative images of positively stained muscle fibers for DAPI, laminin and eMHC from untrained and trained TA muscles (A) and quantification of fibers positive for eMHC as a percentage of total fibers (B). *Significantly different from untrained, P = 0.031.
Fig. 10.
Fig. 10.
Six isometric training sessions over 4 wk results in a greater number of satellite cells in the tibialis anterior (TA) muscle of mdx mice (n = 8). Representative flow cytometric analysis of satellite cells double positive for VCAM and alpha7 integrin from untrained and trained TA muscles normalized to TA muscle mass (A) and satellite cell number normalized to TA mass (B). *Significantly different from untrained, P = 0.041.
Fig. 11.
Fig. 11.
Six isometric training sessions over 4 wk results in a partial protection of isolated extensor digitorum longus (EDL) muscle from eccentric contraction-induced force loss. Eccentric force as a percentage of the first contraction of untrained and trained EDL muscle during five eccentric contractions (A) and isometric tetanic force of EDL muscles immediately following the 5th eccentric contraction relative to isometric force before the eccentric contractions (B). *Significantly different from untrained, P = 0.030. n = 5/group.

Similar articles

See all similar articles

Cited by 1 article

Publication types

MeSH terms

LinkOut - more resources

Feedback