Muscular dystrophy in PTFR/cavin-1 null mice
Shi-Ying Ding, Libin Liu, Paul F. Pilch
Shi-Ying Ding, Libin Liu, Paul F. Pilch
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Research Article Cell biology Muscle biology

Muscular dystrophy in PTFR/cavin-1 null mice

Abstract

Mice and humans lacking the caveolae component polymerase I transcription release factor (PTRF, also known as cavin-1) exhibit lipo- and muscular dystrophy. Here we describe the molecular features underlying the muscle phenotype for PTRF/cavin-1 null mice. These animals had a decreased ability to exercise, and exhibited muscle hypertrophy with increased muscle fiber size and muscle mass due, in part, to constitutive activation of the Akt pathway. Their muscles were fibrotic and exhibited impaired membrane integrity accompanied by an apparent compensatory activation of the dystrophin-glycoprotein complex along with elevated expression of proteins involved in muscle repair function. Ptrf deletion also caused decreased mitochondrial function, oxygen consumption, and altered myofiber composition. Thus, in addition to compromised adipocyte-related physiology, the absence of PTRF/cavin-1 in mice caused a unique form of muscular dystrophy with a phenotype similar or identical to that seen in humans lacking this protein. Further understanding of this muscular dystrophy model will provide information relevant to the human situation and guidance for potential therapies.

Authors

Shi-Ying Ding, Libin Liu, Paul F. Pilch

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Figure 2

Cavin-1 null mice display constitutively enhanced Akt signaling.

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Cavin-1 null mice display constitutively enhanced Akt signaling. (A) Rep...
(A) Representative Western blot analysis of IGF-1/Akt signaling downstream factors in WT and cavin-1 KO littermates. The experiment was replicated 3 times (6 WT and 6 KO mice). (B) Representative Western blot analysis of IGF-1/Akt signaling downstream factors with IGF-1 stimulation. The graphs show densitometric quantification of Western blots, representing increases (%) of ratios of p-p70S6K/p70S6K, p-S6/S6, p-4EBP1/4EBP1and p-Akt/Akt, under IGF-1 stimulation compared with the ratios at basal status, respectively (n = 4–5 for each group from 3 independent experiments). (C) Representative Akt kinase assay from WT and KO tibialis anterior muscle. Akt was immunoprecipitated from muscle lysates and incubated with substrate and the kinase activity was measured using anti–phospho-GSK3α/β to detect phosphorylation of glycogen synthase kinase (GSK) peptide (Akt substrate, 27 kD). The protein levels of total Akt, p-Akt, total GSK, and p-GSK in whole lysates of the same muscle samples were also detected in parallel in separate gels. The experiment was replicated 3 times. (D) mRNA expression levels of atrophy marker genes Atrogin-1 and MuRF1, and of important muscle growth regulator genes myostatin (Mstn) and Igf1 as measured by quantitative real-time PCR (n = 5–7). Data are represented as mean ± SEM. Bonferroni’s multiple comparison test (B) or 2-tailed Student’s t test (D) were used to determine the statistical significance between WT and KO mice. *P < 0.05, **P < 0.01, ***P < 0.001.