Rapid depletion of muscle progenitor cells in dystrophic mdx/utrophin−/− mice

Abstract

Duchenne muscular dystrophy (DMD) patients lack dystrophin from birth; however, muscle weakness becomes apparent only at 3-5 years of age, which happens to coincide with the depletion of the muscle progenitor cell (MPC) pools. Indeed, MPCs isolated from older DMD patients demonstrate impairments in myogenic potential. To determine whether the progression of muscular dystrophy is a consequence of the decline in functional MPCs, we investigated two animal models of DMD: (i) dystrophin-deficient mdx mice, the most commonly utilized model of DMD, which has a relatively mild dystrophic phenotype and (ii) dystrophin/utrophin double knock-out (dKO) mice, which display a similar histopathologic phenotype to DMD patients. In contrast to age-matched mdx mice, we observed that both the number and regeneration potential of dKO MPCs rapidly declines during disease progression. This occurred in MPCs at both early and late stages of myogenic commitment. In fact, early MPCs isolated from 6-week-old dKO mice have reductions in proliferation, resistance to oxidative stress and multilineage differentiation capacities compared with age-matched mdx MPCs. This effect may potentially be mediated by fibroblast growth factor overexpression and/or a reduction in telomerase activity. Our results demonstrate that the rapid disease progression in the dKO model is associated, at least in part, with MPC depletion. Therefore, alleviating MPC depletion could represent an approach to delay the onset of the histopathologies associated with DMD patients.

Loss of NAD Homeostasis Leads to Progressive and Reversible Degeneration of Skeletal Muscle

“…To determine if the mNKO myopathy worsened over time, as occurs in severe muscular dystrophies (Lu et al, 2014; Sacco et al, 2010), we monitored body weight and endurance as the animals aged. Though equal tibia lengths indicated that mutants were skeletally full grown (Figure S2B), the slight decrease in lean mass observed in 3-month-old male knockouts represented the beginning of a plateau in this parameter, driving a divergence in body weight as control littermates continued to gain weight (Figure 2D, E).…”

Skeletal muscle satellite cells: Mediators of muscle growth during development and implications for developmental disorders

“…Impairment in dystrophin and its associated proteins causes an interruption between the myofiber, its sarcolemma, and the ECM, leading to altered mechanical stress, reduced stiffness, inflammation, and consequent muscle regeneration . Transgenic mouse models for DMD ( mdx , mdx /mTR, mdx / utrophin −/− ) have defined the phenotype of muscle dysfunction in DMD and have been used to evaluate the role of SCs in the progressive weakness associated with DMD . Sacco et al .…”

“…107,108 Transgenic mouse models for DMD (mdx, mdx/mTR, mdx/utrophin 2/2 ) have defined the phenotype of muscle dysfunction in DMD and have been used to evaluate the role of SCs in the progressive weakness associated with DMD. 109 Sacco et al 110 showed that pathological muscle progression in DMD could be related to inability of the SCs to maintain the capacity to repair after multiple damage-repair cycles, specifically early exhaustion of the stem cell pool. Consistent with the idea that dystrophic muscle undergoes multiple cycles of regeneration, it has been shown that telomere shortening 110 occurs in DMD patients' muscles.…”

Comparação do potencial terapêutico de células mesenquimais e pericitos em modelo murino de distrofia muscular

“…Essa linhagem de camundongos foi gerada por dois grupos, de forma independente, com o intuito de verificar a hipótese de que a compensação da distrofina pela utrofina nos camundongos mdx poderia ser a responsável por proporcionar o fenótipo mais leve da doença nestes animais (Deconinck et al 1997;Grady et al 1997 (Lu et al 2014) e também aprofundaram o conhecimento sobre a gravidade das deformações nos tecidos musculoesqueléticos, como osso e cartilagem (Isaac et al 2013), observações consistentes com as alterações em pacientes com DMD.…”

“…Apesar de termos confirmado o resultado anterior utilizando pericitos de tecido adiposo de outra doadora, já foi mostrado que existem subpopulações diferentes de pericitos (Birbrair et al 2013;Birbrair et al 2014): uma população com potencial miogênico e angiogênico e outra com potencial de formação de fibrose. Além disso, mostrou-se que o ambiente muscular que receberá as células também é importante, pois quanto mais velho e lesionado, pior a eficiência das células transplantadas (Birbrair et al 2013;Lu et al 2014). …”