Muscles of mice deficient in alpha-sarcoglycan maintain large masses and near control force values throughout the life span.

alpha-Sarcoglycan-deficient (Sgca-null) mice provide potential for elucidating the pathogenesis of limb girdle muscular dystrophy type 2D (LGMD 2D) as well as for studying the effectiveness of therapeutic strategies. Skeletal muscles of Sgca-null mice demonstrate an early onset of extensive fiber necrosis, degeneration, and regeneration, but the progression of the pathology and the effects on muscle structure and function throughout the life span are not known. Thus the phenotypic accuracy of the Sgca-null mouse as a model of LGMD 2D has not been fully established. To investigate skeletal muscle structure and function in the absence of alpha-sarcoglycan throughout the life span, we analyzed extensor digitorum longus and soleus muscles of male and female Sgca-null and wild-type mice at 3, 6, 12, and 18 mo of age. Maximum isometric forces and powers were measured in vitro at 25 degrees C. Also determined were individual myofiber cross-sectional areas and numbers, water content, and the proportion of the cross section occupied by connective tissue. Muscle masses were 40-100% larger for Sgca-null compared with age- and gender-matched wild-type mice, with the majority of the increased muscle mass for Sgca-null mice attributable to greater connective tissue and water contents. Although the greater mass of muscles in Sgca-null mice was primarily noncontractile material, absolute forces and powers were maintained near control levels at all ages, indicating a successful adaptation to the deficiency in alpha-sarcoglycan not observed at any age in LGMD 2D patients.

Susceptibility to sarcomere injury induced by single stretches of maximally activated muscles of mdx mice.

The purpose was to investigate the contribution of mechanical damage to sarcomeres to the greater susceptibility of dystrophic muscle fibers to contraction-induced injury. Single stretches provide an effective method for studying mechanical factors that contribute to the initiation of contraction-induced injury. We hypothesized that, after single stretches, the deficits in isometric force would be greater for muscles of mdx than C57BL/10 mice, whereas membrane damage would be minimal for all muscles. Extensor digitorum longus (EDL) and soleus muscles of mice were removed under anesthesia with Avertin (tribromoethanol). During the plateau of a maximum isometric contraction in vitro, muscles were stretched through single strains of 20-60% fiber length. Isometric force was remeasured 1 min later, and muscles were then incubated in procion orange dye to identify fibers with membrane damage. Force deficits at 1 min were two- to threefold greater for EDL muscles of mdx compared with C57BL/10 mice, whereas no significant differences were observed between soleus muscles of mdx and C57BL/10 mice. For all muscles, membrane damage was minimal and not significantly increased by single stretches for either strain of mice. These data support a critical role of dystrophin maintaining sarcomere stability in EDL muscles, whereas soleus muscles retain abilities, in the absence of dystrophin, not different from control muscles to resist sarcomere damage.