Human progeroid syndromes and premature aging mouse models present as segmental, accelerated aging because some tissues and not others are affected. Skeletal muscle is detrimentally changed by normal aging but whether it is an affected tissue in progeria has not been resolved. We hypothesized that mice which mimic Hutchinson-Gilford progeria syndrome would exhibit age-related alterations of skeletal muscle. Zmpste24-/- and Zmpste24+/+ littermates were assessed for skeletal muscle functions, histo-morphological characteristics, and ankle joint mechanics. Twenty-four-hour active time, ambulation, grip strength, and whole body tension were evaluated as markers of neuromuscular performance, each of which was at least 33% lower in Zmpste24-/- mice compared with littermates (p<0.06). Contractile capacity of the posterior leg muscles were not affected in Zmpste24-/- mice, but muscles of the anterior leg were 30-90% weaker than those of Zmpste24+/+ mice (p< 0.01). Leg muscles were 32-47% smaller in the Zmpste24-/- mice and contained ~60% greater collagen relative to littermates (p<0.01). Soleus and extensor digitorum longus muscles of Zmpste24-/- mice had excessive myonuclei and altered fiber size distributions but, otherwise, appeared normal. Ankle range of motion was 70% lower and plantar- and dorsiflexion passive torques were nearly 3-fold greater in Zmpste24-/- Than Zmpste24+/+ mice (p=0.01). The combined factors of muscle atrophy, collagen accumulation, and perturbed joint mechanics likely contributed to poor neuromuscular performance and selective muscle weakness displayed by Zmpste24-/-mice. In summary, these characteristics are similar to those of aged mice indicating accelerated aging of skeletal muscle in progeria.
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Acknowledgments The authors would like to thank Stephen Young (University of California, Los Angeles) for the gift of Zmpste24−/− breeders as well as Greg Cochrane, Trevor Keyler, Allison Kosir, Ron McElmurry, and Brandon Peacock for their contributions to this project. The research was supported by the Progeria Research Foundation (J. Tolar) and National Institute of Health grants K02 -AG036827 (D.A. Lowe) and T32-AR07612 (J.A. Call).
- Range of motion