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Dysregulation of matricellular proteins is an early signature of pathology in laminin-deficient muscular dystrophy.

Mehuron T, Kumar A, Duarte L, Yamauchi J, Accorsi A, Girgenrath M - Skelet Muscle (2014)

Bottom Line: We found that DyW mice show significantly impaired myogenesis and high levels of apoptosis as early as postnatal week 1.Interestingly, fibronectin was found to be the predominant fibrous protein of the extracellular matrix in early postnatal development.On the basis of our results, we believe that therapies that may reduce apoptosis and stabilize the homeostasis of extracellular matrix proteins may have increased efficacy if started at a very early age.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Health Sciences, Boston University, 635 Commonwealth Avenue, Boston, MA 02215, USA.

ABSTRACT

Background: MDC1A is a congenital neuromuscular disorder with developmentally complex and progressive pathologies that results from a deficiency in the protein laminin α2. MDC1A is associated with a multitude of pathologies, including increased apoptosis, inflammation and fibrosis. In order to assess and treat a complicated disease such as MDC1A, we must understand the natural history of the disease so that we can identify early disease drivers and pinpoint critical time periods for implementing potential therapies.

Results: We found that DyW mice show significantly impaired myogenesis and high levels of apoptosis as early as postnatal week 1. We also saw a surge of inflammatory response at the first week, marked by high levels of infiltrating macrophages, nuclear factor κB activation, osteopontin expression and overexpression of inflammatory cytokines. Fibrosis markers and related pathways were also observed to be elevated throughout early postnatal development in these mice, including periostin, collagen and fibronectin gene expression, as well as transforming growth factor β signaling. Interestingly, fibronectin was found to be the predominant fibrous protein of the extracellular matrix in early postnatal development. Lastly, we observed upregulation in various genes related to angiotensin signaling.

Methods: We sought out to examine the dysregulation of various pathways throughout early development (postnatal weeks 1-4) in the DyW mouse, the most commonly used mouse model of laminin-deficient muscular dystrophy. Muscle function tests (stand-ups and retractions) as well as gene (qRT-PCR) and protein levels (western blot, ELISA), histology (H&E, picrosirius red staining) and immunohistochemistry (fibronectin, TUNEL assay) were used to assess dysregulation of matricelluar protieins.

Conclusions: Our results implicate the involvement of multiple signaling pathways in driving the earliest stages of pathology in DyW mice. As opposed to classical dystrophies, such as Duchenne muscular dystrophy, the dysregulation of various matricellular proteins appears to be a distinct feature of the early progression of DyW pathology. On the basis of our results, we believe that therapies that may reduce apoptosis and stabilize the homeostasis of extracellular matrix proteins may have increased efficacy if started at a very early age.

No MeSH data available.


Related in: MedlinePlus

Overall body and isolated hindlimb muscle weights show limited growth in DyW mice during postnatal development. (A) At postnatal weeks 1 and 2, Lama2DyW (DyW) mice had body weights to comparable those of wild-type (WT) mice, but were significantly smaller starting at week 3 (P < 0.05 by t-test (n = 5 to 10). (B) Tibialis anterior (TA), (C) gastrocnemius/soleus (GS) and (D) quadriceps (QD) muscles of DyW mice were also significantly smaller in weight compared to WT mice starting from 3 weeks of age (P < 0.0005 by analysis of variance (n = 6 to 10)). Asterisks indicate statistical significance between age-matched DyW and WT animals; hash tags indicate statistically significant changes within the DyW group; Delta indicates statistically significant changes within the WT group. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. These statistical representations also apply to the other symbols (Δ, #).
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Figure 1: Overall body and isolated hindlimb muscle weights show limited growth in DyW mice during postnatal development. (A) At postnatal weeks 1 and 2, Lama2DyW (DyW) mice had body weights to comparable those of wild-type (WT) mice, but were significantly smaller starting at week 3 (P < 0.05 by t-test (n = 5 to 10). (B) Tibialis anterior (TA), (C) gastrocnemius/soleus (GS) and (D) quadriceps (QD) muscles of DyW mice were also significantly smaller in weight compared to WT mice starting from 3 weeks of age (P < 0.0005 by analysis of variance (n = 6 to 10)). Asterisks indicate statistical significance between age-matched DyW and WT animals; hash tags indicate statistically significant changes within the DyW group; Delta indicates statistically significant changes within the WT group. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. These statistical representations also apply to the other symbols (Δ, #).

Mentions: We began our characterization of this animal model by tracking overall body and hindlimb muscle weights throughout early postnatal development. DyW and WT mice had similar body weights at 1 week (DyW: 4.51 ± 0.8 g, n = 8; WT: 5.92 ± 1.10 g, n = 5) and 2 weeks (DyW: 5.83 ± 0.821, n = 9; WT: 6.72 ± 0.52 g, n = 6) after birth (Figure 1A). WT mice then underwent a substantial growth spurt between weeks 2 and 4 (3 weeks: 12.54 ± 2.54 g; 4 weeks: 17.43 ± 1.91 g; P < 0.001 by two-way ANOVA (n = 6 to 10)), whereas DyW mice failed to substantially grow (3 weeks: 6.53 ± 1.83 g, 4 weeks: 7.76 ± 2.15 g). It should be noted that other research groups saw statistical differences in body size at postnatal day 7, though these differences were still small [17].


Dysregulation of matricellular proteins is an early signature of pathology in laminin-deficient muscular dystrophy.

Mehuron T, Kumar A, Duarte L, Yamauchi J, Accorsi A, Girgenrath M - Skelet Muscle (2014)

Overall body and isolated hindlimb muscle weights show limited growth in DyW mice during postnatal development. (A) At postnatal weeks 1 and 2, Lama2DyW (DyW) mice had body weights to comparable those of wild-type (WT) mice, but were significantly smaller starting at week 3 (P < 0.05 by t-test (n = 5 to 10). (B) Tibialis anterior (TA), (C) gastrocnemius/soleus (GS) and (D) quadriceps (QD) muscles of DyW mice were also significantly smaller in weight compared to WT mice starting from 3 weeks of age (P < 0.0005 by analysis of variance (n = 6 to 10)). Asterisks indicate statistical significance between age-matched DyW and WT animals; hash tags indicate statistically significant changes within the DyW group; Delta indicates statistically significant changes within the WT group. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. These statistical representations also apply to the other symbols (Δ, #).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4114446&req=5

Figure 1: Overall body and isolated hindlimb muscle weights show limited growth in DyW mice during postnatal development. (A) At postnatal weeks 1 and 2, Lama2DyW (DyW) mice had body weights to comparable those of wild-type (WT) mice, but were significantly smaller starting at week 3 (P < 0.05 by t-test (n = 5 to 10). (B) Tibialis anterior (TA), (C) gastrocnemius/soleus (GS) and (D) quadriceps (QD) muscles of DyW mice were also significantly smaller in weight compared to WT mice starting from 3 weeks of age (P < 0.0005 by analysis of variance (n = 6 to 10)). Asterisks indicate statistical significance between age-matched DyW and WT animals; hash tags indicate statistically significant changes within the DyW group; Delta indicates statistically significant changes within the WT group. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. These statistical representations also apply to the other symbols (Δ, #).
Mentions: We began our characterization of this animal model by tracking overall body and hindlimb muscle weights throughout early postnatal development. DyW and WT mice had similar body weights at 1 week (DyW: 4.51 ± 0.8 g, n = 8; WT: 5.92 ± 1.10 g, n = 5) and 2 weeks (DyW: 5.83 ± 0.821, n = 9; WT: 6.72 ± 0.52 g, n = 6) after birth (Figure 1A). WT mice then underwent a substantial growth spurt between weeks 2 and 4 (3 weeks: 12.54 ± 2.54 g; 4 weeks: 17.43 ± 1.91 g; P < 0.001 by two-way ANOVA (n = 6 to 10)), whereas DyW mice failed to substantially grow (3 weeks: 6.53 ± 1.83 g, 4 weeks: 7.76 ± 2.15 g). It should be noted that other research groups saw statistical differences in body size at postnatal day 7, though these differences were still small [17].

Bottom Line: We found that DyW mice show significantly impaired myogenesis and high levels of apoptosis as early as postnatal week 1.Interestingly, fibronectin was found to be the predominant fibrous protein of the extracellular matrix in early postnatal development.On the basis of our results, we believe that therapies that may reduce apoptosis and stabilize the homeostasis of extracellular matrix proteins may have increased efficacy if started at a very early age.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Health Sciences, Boston University, 635 Commonwealth Avenue, Boston, MA 02215, USA.

ABSTRACT

Background: MDC1A is a congenital neuromuscular disorder with developmentally complex and progressive pathologies that results from a deficiency in the protein laminin α2. MDC1A is associated with a multitude of pathologies, including increased apoptosis, inflammation and fibrosis. In order to assess and treat a complicated disease such as MDC1A, we must understand the natural history of the disease so that we can identify early disease drivers and pinpoint critical time periods for implementing potential therapies.

Results: We found that DyW mice show significantly impaired myogenesis and high levels of apoptosis as early as postnatal week 1. We also saw a surge of inflammatory response at the first week, marked by high levels of infiltrating macrophages, nuclear factor κB activation, osteopontin expression and overexpression of inflammatory cytokines. Fibrosis markers and related pathways were also observed to be elevated throughout early postnatal development in these mice, including periostin, collagen and fibronectin gene expression, as well as transforming growth factor β signaling. Interestingly, fibronectin was found to be the predominant fibrous protein of the extracellular matrix in early postnatal development. Lastly, we observed upregulation in various genes related to angiotensin signaling.

Methods: We sought out to examine the dysregulation of various pathways throughout early development (postnatal weeks 1-4) in the DyW mouse, the most commonly used mouse model of laminin-deficient muscular dystrophy. Muscle function tests (stand-ups and retractions) as well as gene (qRT-PCR) and protein levels (western blot, ELISA), histology (H&E, picrosirius red staining) and immunohistochemistry (fibronectin, TUNEL assay) were used to assess dysregulation of matricelluar protieins.

Conclusions: Our results implicate the involvement of multiple signaling pathways in driving the earliest stages of pathology in DyW mice. As opposed to classical dystrophies, such as Duchenne muscular dystrophy, the dysregulation of various matricellular proteins appears to be a distinct feature of the early progression of DyW pathology. On the basis of our results, we believe that therapies that may reduce apoptosis and stabilize the homeostasis of extracellular matrix proteins may have increased efficacy if started at a very early age.

No MeSH data available.


Related in: MedlinePlus