Making fast-twitch dystrophic muscles bigger protects them from contraction injury and attenuates the dystrophic pathology.
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 beta-agonist formoterol (100 microg/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.
Gehrig
Stefan M
SM
Basic and Clinical Myology Laboratory, Department of Physiology, The University of Melbourne, Victoria 3010, Australia. gsl@unimelb.edu.au
Koopman
René
R
Naim
Timur
T
Tjoakarfa
Clarissa
C
Lynch
Gordon S
GS
D000818:Animals; D004983:Ethanolamines / Q000494:pharmacology; D000068759:Formoterol Fumarate; D051379:Mice; D018101:Mice, Inbred mdx; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D018656:Muscle Fibers, Fast-Twitch / Q000187:drug effects / Q000473:pathology*; D009137:Muscular Dystrophy, Animal / Q000473:pathology* / Q000503:physiopathology*; D009929:Organ Size / Q000187:drug effects
D004983:Ethanolamines; D000068759:Formoterol Fumarate