Skeletal Muscle Contractile Properties in a Novel Murine Model for Limb Girdle Muscular Dystrophy 2i

Limb-girdle muscular dystrophy (LGMD) 2i results from mutations in fukutin-related protein and aberrant α-dystroglycan glycosylation. Although this significantly compromises muscle function and ambulation, the comprehensive characteristics of contractile dysfunction are unknown. We therefore quantified the in situ contractile properties of the medial gastrocnemius in young adult P448L mice, an affected muscle and novel model of LGMD2i, respectively. Maximal twitch force, tetanic force and power normalized to physiological cross-sectional area were significantly smaller in P448L mice, compared to sex-matched wild-type mice. These differences were consistent with the replacement of contractile fibers by passive tissue. The shape of the active force-length relationships were similar in both groups, regardless of sex, consistent with intact sarcomere homogeneity in P448L mice. Passive force-length curves normalized to maximal isometric force were steeper in P448L mice and passive elements contribute disproportionately more to total contractile force in P448L mice. Sex differences were mostly noted in the force-velocity curves as normalized values for maximal and optimal velocities were significantly slower in P448L males, compared to wild-type, but not in P448L females. This suggests that the dystrophic phenotype, which may include possible changes in cross-bridge kinetics and fiber type proportions, progresses more quickly in P448L males. These results together indicate that active force and power generation are compromised in both sexes of P448L mice while passive forces increase. More importantly, the results identified several functional markers of disease pathophysiology that could aid in developing and assessment of novel therapeutics for LGMD2i and possibly other dystroglycanopathies as well.

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