The Role of Lipin1 in Myofiber Stability and Integrity - PROJECT SUMMARY
Duchenne muscular dystrophy (DMD) is a progressive and devastating muscle disease, resulting from the
absence of dystrophin. This leads to cell membrane instability, susceptibility to contraction-induced muscle
damage, muscle cell death, and disability and early death of patients. Currently, there is no cure for DMD.
Lipin1 is a phosphatidic acid (PA) phosphatase (PAP) enzyme that catalyzes diacylglycerol (DAG)
biosynthesis. It is also the predominant lipin isoform in skeletal muscles. In addition to its enzymatic activity,
lipin1 can regulate transcription. A recent publication from this lab identified a previously unknown role of lipin1
in promoting myocyte enhancer factor 2c (MEF2c) transcriptional activity via DAG signaling in skeletal muscle.
Notably, our findings showed that loss of lipin1 leads to myopathy. Preliminary data also showed that lipin1
expression was dramatically reduced in the skeletal muscles of DMD patients and mdx (DMDmdx) mice, a
mouse model for DMD. Strikingly, further data show that increasing lipin1 levels in mdx mice lessened muscle
fiber degeneration, strengthened membrane integrity, and led to impressive gains in strength. Based on these
novel findings, the central hypothesis of this proposal is that lipin1 overexpression ameliorates the dystrophic
phenotype in DMD through its PAP activity and its ability to regulate transcription. This hypothesis will be
tested via the following Specific Aims: 1) Assess the pathological and functional benefit of lipin1
overexpression in mdx:lipin1 transgenic mice in early and late stages of the disease; 2) Determine the
therapeutic efficacy of AAV9-mediated systemic lipin1 gene delivery; and 3) Test the hypothesis that lipin1
regulates muscle membrane integrity through the transcriptional regulation of structural genes and through
PAP activity.
NIH Mission Relevance: DMD affects 15.9-19.5 individuals per 100,000 live births. Specifically, DMD patients
often manifest disability around age 3-5, and many require a wheelchair before age 12. Progressive muscle
weakness often results in early mortality around age 30. This research seeks to elucidate the role of lipin1 as a
novel regulator to prevent dystrophic pathologies, and will determine whether lipin1 can serve as a target to re-
establish membrane stability and restore muscle function. Such information is expected to have a
transformative impact on the treatment of DMD, as well as open new avenues for the treatment of several
clinically related conditions, such as rhabdomyolysis, age-related muscle loss, and other muscular dystrophies
which share common features associated with decreased lipin1 expression.
