Frequency decoding in muscle cells; a key for muscle plasticity
Mechanisms of frequency decoding are major question in physiology and biophysics. A train of action potentials at a defined frequency is a code that excitable cells decipher to activate different process that determine their behavior. Different stimulation patterns activate diverse signaling pathways in skeletal muscle fibers that ultimately define their phenotype. We will disclose the molecular mechanism by which the voltage sensor domains of the α1 subunit of the Cav1.1 molecule, distinguish the frequency of action potentials in the transverse tubule membrane of the skeletal muscle fiber in order to activate distinct signaling pathways leading to adaptation of the fiber to the exercise demands. This is a fundamental mechanism to explain skeletal muscle adaptation.
Excitation-Metabolism coupling in skeletal muscle
Excitation-metabolism (E-M) coupling is the ensemble of mechanisms by which electrical stimulation of skeletal muscle transduce into metabolic changes in the muscle fiber. These mechanisms are idly known and in most part assumed but have not been tested. Our aim is to understand the cellular basis of the link between electrical stimulation of the muscle cell (one of the constant features of exercise) and the short and long term metabolic adaptations of skeletal muscle as well as the alterations of this process that occur upon metabolic challenges in obesity and aging. The role of oxidative signals in glucose transport, mitochondria calcium signaling and their role in regulating mitochondria function and the regulation of metabolic genes expression are part of this study.
Role of membrane cholesterol in muscle cell signaling
Insulin resistance (IR) is associated to the development of syndromes such as obesity, metabolic syndrome and type 2 diabetes. Alterations in glucose homeostasis, due to deficient GLUT4 translocation and lowered insulin sensitivity in muscle, characterize IR. Skeletal muscle is the main source of GLUT4-mediated glucose transport in animals; in fact, this tissue removes ca. 80% of circulating glucose after a meal. Most GLUT4-mediated glucose transport occurs in the transverse tubules (TT), a specialized plasma membrane system of skeletal muscle. The TT membrane is highly enriched in cholesterol; and we found that cholesterol levels in skeletal muscle are higher in IR mice. We have shown that the cholesterol-lowering agent methyl- β-cyclodextrin affects GLUT4 trafficking and glucose uptake in adult muscle fibers and we will show that ABCA1, a transporter that mediates cellular cholesterol efflux, has a role in regulating cholesterol content, glucose tolerance and insulin sensitivity in skeletal muscle.
Designing new pharmacological tools to target muscular dystrophy and aging sarcopenia
Sarcopenia is the loss of skeletal muscle mass with age and affects 100% of the population, becoming invalidating for between 20% and 50% of people older than 80. Duchenne muscular dystrophy is an inherited neuromuscular disease affecting one in 3300 newborn human males. There is no effective treatment for either muscular dystrophy or sarcopenia so far.
In a mouse model of Duchenne muscular dystrophy (mdx), presenting some features of the human illness, we have shown that the use of dihydropyridines (DHP, Nifedipine) show an impressing recovery of muscle function with a significant reduction in muscle damage and a restored normal gene expression in the muscle fibers. The symptoms improvement is associated with the normalization of ATP release from muscle fibers. We are testing and designing new DHPs to treat both muscular dystrophy and sarcopenia, aiming to design a therapy to be tested in human patients.