Long-term enhancement of skeletal muscle mass and strength by single gene administration of myostatin inhibitors - PubMed (original) (raw)

Long-term enhancement of skeletal muscle mass and strength by single gene administration of myostatin inhibitors

Amanda M Haidet et al. Proc Natl Acad Sci U S A. 2008.

Abstract

Increasing the size and strength of muscles represents a promising therapeutic strategy for musculoskeletal disorders, and interest has focused on myostatin, a negative regulator of muscle growth. Various myostatin inhibitor approaches have been identified and tested in models of muscle disease with varying efficacies, depending on the age at which myostatin inhibition occurs. Here, we describe a one-time gene administration of myostatin-inhibitor-proteins to enhance muscle mass and strength in normal and dystrophic mouse models for >2 years, even when delivered in aged animals. These results demonstrate a promising therapeutic strategy that warrants consideration for clinical trials in human muscle diseases.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

Myostatin inhibitor proteins increase muscle mass and strength in wild-type C57BL/6 mice. (a) Gross hindlimb muscle mass is increased in all myostatin-inhibitor-protein treated mice at 725 days of age compared with AAV1-GFP injected controls. (b) Total body mass is significantly increased in AAV1-FS-injected (**, P ≤ 0.01) and AAV1-GASP-1-injected (*, P ≤ 0.05) mice compared with AAV1-GFP controls at 725 days of age (n = 10). (c) The mass of individual hindlimb and forelimb muscles is increased in mice injected with AAV expressing myostatin inhibitor proteins (n = 10). *, P ≤ 0.05. (d) Hindlimb grip strength improves >2 years in all treated mice with the greatest differences in AAV1-FS treated animals compared with AAV1-GFP controls (n = 10). Error bars represent standard error.

Fig. 2.

Fig. 2.

Single injection of AAV1-FS increases muscle mass and strength in young mdx mice. (a) Gross hindlimb muscle mass is increased in AAV1-FS-injected mdx animals at 180 days of age compared with AAV1-GFP-injected controls. (b) The mass of individual hindlimb and forelimb muscles is increased at 180 days of age in mice injected at 3 weeks of age with AAV1-FS compared with AAV1-GFP controls (n = 15). *, P ≤ 0.05. (c) Grip strength is improved in a dose-dependent manner in young mdx mice injected at 3 weeks of age with AAV1-FS followed for 180 days (n = 15). Red, high-dose AAV1-FS; blue, low- dose AAV1-FS; green, AAV1-GFP controls. Error bars represent standard errors.

Fig. 3.

Fig. 3.

mdx mice treated with AAV1-FS at 3 weeks of age and followed for 180 days demonstrate myofiber hypertrophy. (a) H&E staining of the tibialis anterior reveals myofiber hypertrophy in AAV1-FS injected muscle compared with AAV1-GFP control. (Original magnification, ×40.) (b) The mean diameter of dark (slow-twitch oxidative), intermediate (fast-twitch oxidative glycolytic), and light (fast twitch glycolytic) myofibers in the tibialis anterior (indicated by hatched line) is significantly increased in mice injected with AAV1-FS compared with AAV1-GFP-injected controls. (P < 0.001; _n_ = 5). (_c_) The mean diameter of intermediate and light myofibers (indicated by hatched line) in the triceps is significantly increased in mice injected with AAV1-FS compared with AAV1-GFP-injected controls. (_P_ < 0.001; _n_ = 5.) (_d_) The distribution of dark, intermediate, and light fibers as determined by succinic dehydrogenase (SDH) staining is not changed by treatment with high or low doses of AAV1-FS. (_P_ > 0.05 between all groups; n = 5.) (e) The mean number of fibers counted per an unbiased 0.14 mm2 counting frame is decreased in the tibialis anterior of AAV1-FS-treated mice, given that the mean diameter of myofibers is increased. (*, P < 0.01; n = 5.) Error bars represent standard errors.

Fig. 4.

Fig. 4.

mdx mice treated with AAV1-FS show decreased markers of muscle damage and aged mdx mice are responsive to FS treatment with functional benefit. (a) Serum creatine kinase levels (units/liter) are decreased at 3 months after injection with AAV1-FS compared with AAV1-GFP-injected controls. (*, P < 0.05; n = 10.) Error bars represent standard errors. (b) Hindlimb grip strength is significantly increased (P ≤ 0.05) at 275 days and beyond in aged mdx mice treated with AAV1-FS at 210 days of age (n = 15). Red, high-dose AAV1-FS; green, AAV1-GFP controls. (c) H&E stain of aged gastrocnemius demonstrates reduced pathology when injected at 210 days of age with FS compared with GFP-injected controls. (Original magnification, ×40.) (d) H&E stained diaphragm of animals injected at 210 days of age with FS shows less fat replacement than GFP-injected controls at late stage. (Original magnification, ×20.)

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