The Leinwand Lab: Unraveling mechanisms of genetic heart and skeletal muscle diseases
Numerous motor and structural proteins compose a highly ordered structure known as the sarcomere, the basic unit of muscle contraction in heart and skeletal muscles. Sarcomeric myosin heavy chain proteins are the molecular motors responsible for muscle contraction. Mutations in these proteins perturb their interactions with other proteins and their function, which leads to disease.
Research in the Leinwand lab focuses on unraveling mechanisms of genetic heart and skeletal muscle diseases using animal models, cell-culture systems and biophysical approaches. In addition to assessing mutations in myosin proteins that lead to disease, we also work to understand physiologic heart muscle growth and loss using mouse and python as model organisms as well as fundamental differences in heart biology between males and females.
Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are two major forms of heart disease. In DCM, the heart’s chambers enlarge, thinning the walls of those chambers. As a result, the heart does not contract or pump blood well. In HCM, the heart’s walls thicken, resulting in smaller chambers. Here the heart muscle must work harder to pump an adequate volume of blood. HCM is a severe genetic heart disease and is the leading cause of sudden death in young athletes.
in cases of HCM, mutations in myosin heavy chain proteins are found throughout the protein, yet many lead to the same clinical diagnosis. This suggests that a general disruption of protein structure could underlie this and other pathologies. Several projects in the lab assess the effects of individual mutations on protein function, incorporation into the sarcomere and overall heart function. Using animal models in conjunction with cell-based studies is essential for determining which disease traits are due to direct effects of mutations and which are due to secondary or tertiary effects of the progressing disease state.
A relatively recently identified member of the “sarcomeric” myosin gene family, called MYH7b, is found in a number of nonmuscle tissues which is very unusual, and people in the lab are trying to understand how this myosin functions in a nonmuscle cellular environment.
A key molecular chaperone (called Unc45b) folds the myosin protein so that it maintains a functional shape. Another project in the lab seeks to identify additional possible molecules that help to arrange and maintain the appropriate myosin heavy chain protein shape and aid its incorporation into the sarcomere, as well as how mutations in the gene for this protein may disrupt these attributes.
Heart disease causes stiffening, known as fibrosis, of the otherwise flexible organ. Fibrosis impairs the heart’s ability to contract and can exacerbate pre-existing heart conditions. In collaboration with Dr. Kristi Anseth’s lab in the Chemical & Biological Engineering department, we work to determine how a stiff environment affects muscle cell function and signaling.
Despite expansive knowledge and decades-long study of the sarcomeric myosin heavy chain protein family, much remains unknown. Because of their necessity to cellular function and organism health, it is essential to understand the full repertoire of this protein family. In addition to understanding how mutations in different myosin proteins lead to disease, we also work to uncover the function of all members of this protein family, including two newly-discovered ones.
Another active area of research in the laboratory focuses on unraveling the mechanisms behind maladaptive, or pathological, and adaptive, or physiological, cardiac hypertrophy. In response to certain stresses, such as exercise and pregnancy, physiological cardiac hypertrophy can develop but is often fully reversible upon removal of the stimuli. In contrast, pathological hypertrophy, often a result of hypertension, aortic valve stenosis, or chronic adrenergic receptor stimulation, is considered irreversible even when the pathological stimulus is removed or corrected. Both forms of cardiac hypertrophy differ in their structural and molecular profiles.
To uncover the mechanisms involved in both the development of cardiac hypertrophy, and the regression from this hypertrophic state, the laboratory uses several different model systems including the Burmese python. The Burmese python undergoes significant cardiac hypertrophy following consumption of a large meal. Within 10-15 days, the adaptive cardiac hypertrophy within the Burmese python fully regresses and is no longer significantly bigger compared to fasted controls. Thus, along with pregnancy and exercise models, we utilize the Burmese python as a model of physiological hypertrophy.
To contrast our models of physiological hypertrophy, we employ several different models of pathological hypertrophy. These include acute or chronic adrenergic stimulation, high-fat (or Western) diets, pressure overload, and myocardial infarction models. Using both physiological and pathological model systems, we are able to compare and contrast the pathology underscoring both classifications of cardiac hypertrophy.