Ma Lab Research

Ca signaling in apoptosis of cancer cells: Apoptosis, an evolutionarily conserved programmed cell death process, plays a crucial role in development and tumor regression. Many studies have shown that alteration of intracellular Ca homeostasis (e.g. depletion of ER Ca and/or elevation of cytosolic Ca through store-operated Ca entry) leads to apoptosis in a variety of cells. Bax is a pro-apoptotic member of the Bcl-2 family and its translocation from cytosol to intracellular membrane induces cytochrome c release and triggers the caspase-cascade of ordered cell death. Our studies have shown that Bax and Ca act synergistically to affect the functions of mitochondria and endoplasmic reticulum in the initiation of apoptosis, and endogenous co-factors exist in a prostate cancer cell line NRP-154 that could interact with Bax and render them resistant to apoptosis. A 22 amino acid presenilin loop peptide (PLP), an intermediate apoptosis byproduct, can alter intracellular Ca release and amplify the signaling cascade of apoptosis. As illustrated above, our current research interest focuses on understanding how SOCE contributes to the growth and death of cells by detecting a balanced retrograde signal from the ER to the cytosol and to the plasma membrane.

Ca sparks as an index of muscle health, aging and dystrophy: During aging skeletal muscle become weaker and hundreds of millions of individuals become afflicted by a condition named sarcopenia. While some of the changes that take place in aged skeletal muscles are directly related to muscle atrophy, changes in contractile apparatus function cannot fully explain the decrease in the specific force during aging. Our recent studies revealed that muscle aging is associated with compromised Ca spark signaling, the elemental process of RyR-mediated Ca release, accompanied with the development of a segregated Ca pool that uncouples for the normal E-C coupling process. In addition, we have recently discovered that store-operated calcium entry is significantly compromised in aged skeletal. The model below illustrates some of our current thoughts on this critical issue. As Ca entry is chronically reduced in aged muscle fibers, Ca storage in the SR decreases making less Ca available for each contraction-relaxation cycle, leading to reduced contractile force. Our research involves the use of genetically modified mouse models. One example is shown in the attached move, which illustrates that knockout of MG29 leads to increased susceptibility of the skeletal muscle to fatigue (see movie).

Excitation-contraction (E-C) coupling is a cellular signaling process by which a depolarization signal from a motor neuron results in the contraction of a muscle fiber. Contraction is induced by a global release of Ca from the sarcoplasmic reticulum (SR) into the cytoplasm through the ryanodine receptor Ca release channel. At an elemental level, discreet Ca release events called Ca sparks comprise this global Ca release. In order to terminate contraction, the majority of the released Ca returns to the SR with a minority of the Ca leaking from cell. Store-operated Ca entry acts to replenish this Ca lost from cellular stores and maintains cellular homeostasis. Using an extensive immuno-proteomic approach, our research group has identified and characterized the function of several novel components of the molecular machinery that regulates E-C coupling in muscle physiology and pathophysiology (in collaboration with Dr. Hiroshi Takeshima at Kyoto University).

Major Grant Supports

Role of MG29 in E-C coupling of striated muscles

Store-operated calcium entry and apoptosis

Bidirectional Ca signaling between cell surface and I\intracellular membranes

Ca sparks in muscle aging and dystrophy

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