title: Skeletal muscle contractile function and neuromuscular performance in Zmpste24 -/- mice, a murine model of human progeria.
abstract: 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.
authors.affiliation: Rehabilitation Science and Program in Physical Therapy, University of Minnesota, School of Medicine, 420 Delaware Street SE, Minneapolis, MN 55455, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Greising
authors.forename: Jarrod A
authors.initials: JA
authors.lastname: Call
authors.forename: Troy C
authors.initials: TC
authors.lastname: Lund
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: Jakub
authors.initials: J
authors.lastname: Tolar
authors.forename: Dawn A
authors.initials: DA
authors.lastname: Lowe
mesh_terms: D019588:Aging, Premature / Q000235:genetics; D000818:Animals; D000843:Ankle Joint / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008666:Metalloendopeptidases / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009119:Muscle Contraction / Q000502:physiology*; D053580:Muscle Strength / Q000235:genetics* / Q000502:physiology; D018482:Muscle, Skeletal / Q000473:pathology* / Q000648:ultrastructure; D009469:Neuromuscular Junction / Q000502:physiology* / Q000648:ultrastructure; D010805:Physical Conditioning, Animal; D011371:Progeria / Q000235:genetics*; D011897:Random Allocation; D016059:Range of Motion, Articular / Q000502:physiology; D012016:Reference Values; D012680:Sensitivity and Specificity; D013647:Task Performance and Analysis
chemical_list: D008565:Membrane Proteins; D008666:Metalloendopeptidases; C120130:ZMPSTE24 protein, human