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.Keywords Aging . Lamin . Range of motion . Sarcopenia . Strength Abbreviations EDLExtensor digitorum longus HGPS Hutchinson-Gilford progeria syndrome P o Maximal isometric tetanic force ROM Range of motion AGE (2012) 34:805-819

Lamin Mutations Accelerate Aging via Defective Export of Mitochondrial mRNAs through Nuclear Envelope Budding

“…However, PS patients commonly have decreased NMJ performance[27], defects in the enteric nervous system[28], low-frequency conductive hearing loss, and peripheral neuropathy[29]. Thus, synaptic dysfunction in PS patients cannot be completely ruled out.…”

Muscle-derived stem/progenitor cell dysfunction in Zmpste24-deficient progeroid mice limits muscle regeneration

“…Numerous studies have reported that mutation of lamin A, a major component of the nuclear envelope, has an adverse effect on skeletal muscle function and myoblast differentiation [7,9,11-14,34]; however, no studies examined earlier muscle stem/progenitor cells residing in muscle tissue. Because degenerative changes associated with progeroid syndromes may have a strong impact on stem cells, we hypothesized that the dysfunction of muscle stems cells in Zmpste24 -/- progeroid mice may contribute to the loss of the cells' ability to regenerate skeletal muscle.…”

“…By knocking out Zmpste24 , prelamin A accumulates on the cell nuclear envelope, resulting in cellular blebbing [9,10]. The Zmpste24 -/- mice display accelerated aging, loss of weight, spontaneous bone fracture, cardiomyopathy, muscular dystrophy, muscle atrophy, and muscle weakness [6,7,9,11]. A recent study provides evidence that the skeletal muscles of Zmpste24 -/- mice exhibit impaired muscle contraction and neuromuscular performance [11].…”

Dominant Lethal Pathologies in Male Mice Engineered to Contain an X-Linked DUX4 Transgene

“…For histology, muscles were embedded in OCT. 10 μm sections were evaluated by hematoxylin and eosin (H&E) staining, NADH reactivity, and myosin heavy chain expression as described (Greising et al, 2012). …”