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Key Points Physiological hypertrophy is an adaptive form of cardiac hypertrophy that does not lead to heart disease in healthy individuals. This cardiac growth maintains or augments cardiac function and increases angiogenesis and metabolism. Physiological hypertrophy does not promote fibrotic remodelling or cardiomyocyte death. Physiological hypertrophy is initiated by specific hormones (triiodothyronine, insulin, insulin-like growth factor 1 and vascular endothelial growth factor) or stretch (loading), which activate a restricted number of intracellular signalling pathways (PI3K, AKT, mTOR and ERK1/2). Metabolic reprogramming governed by AMP-activated protein kinase (AMPK) is essential for adaptive cardiac hypertrophy. Exercise induced hypertrophy causes a downregulation of CCAAT/enhancer binding protein-β and the transcription of an exercise-specific gene set. Intermittent PI3K, AKT, ERK1/2 or AMPK activation promotes the activation of a physiological hypertrophic programme to maintain or augment function, thus antagonizing pathological conditions. The heart undergoes physiological hypertrophy in response to developmental signals and increased workload. The structural and molecular characteristics of physiological cardiac hypertrophy are now being elucidated, as are the endocrine effectors and associated signalling pathways that regulate it. The heart hypertrophies in response to developmental signals as well as increased workload. Although adult-onset hypertrophy can ultimately lead to disease, cardiac hypertrophy is not necessarily maladaptive and can even be beneficial. Progress has been made in our understanding of the structural and molecular characteristics of physiological cardiac hypertrophy, as well as of the endocrine effectors and associated signalling pathways that regulate it. Physiological hypertrophy is initiated by finite signals, which include growth hormones (such as thyroid hormone, insulin, insulin-like growth factor 1 and vascular endothelial growth factor) and mechanical forces that converge on a limited number of intracellular signalling pathways (such as PI3K, AKT, AMP-activated protein kinase and mTOR) to affect gene transcription, protein translation and metabolism. Harnessing adaptive signalling mediators to reinvigorate the diseased heart could have important medical ramifications.

Fibroblasts are a dynamic cell type that achieve selective differentiated states to mediate acute wound healing and long-term tissue remodeling with scarring. With myocardial infarction injury, cardiomyocytes are replaced by secreted extracellular matrix proteins produced by proliferating and differentiating fibroblasts. Here, we employed 3 different mouse lineage-tracing models and stage-specific gene profiling to phenotypically analyze and classify resident cardiac fibroblast dynamics during myocardial infarction injury and stable scar formation. Fibroblasts were activated and highly proliferative, reaching a maximum rate within 2 to 4 days after infarction injury, at which point they expanded 3.5-fold and were maintained long term. By 3 to 7 days, these cells differentiated into myofibroblasts that secreted abundant extracellular matrix proteins and expressed smooth muscle α-actin to structurally support the necrotic area. By 7 to 10 days, myofibroblasts lost proliferative ability and smooth muscle α-actin expression as the collagen-containing extracellular matrix and scar fully matured. However, these same lineage-traced initial fibroblasts persisted within the scar, achieving a new molecular and stable differentiated state referred to as a matrifibrocyte, which was also observed in the scars of human hearts. These cells express common and unique extracellular matrix and tendon genes that are more specialized to support the mature scar.

Cardiovascular disease is the number one cause of mortality in the Western world. The heart responds to many cardiopathological conditions with hypertrophic growth by enlarging individual myocytes to augment cardiac pump function and decrease ventricular wall tension. Initially, such cardiac hypertrophic growth is often compensatory, but as time progresses these changes become maladaptive. Cardiac hypertrophy is the strongest predictor for the development of heart failure, arrhythmia, and sudden death. Here we discuss therapeutic avenues emerging from molecular and genetic studies of cardiovascular disease in animal models. The majority of these are based on intracellular signaling pathways considered central to pathologic cardiac remodeling and hypertrophy, which then leads to heart failure. We focus our discussion on selected therapeutic targets that have more recently emerged and have a tangible translational potential given the available pharmacologic agents that could be readily evaluated in human clinical trials.

Cardiac fibroblasts convert to myofibroblasts with injury to mediate healing after acute myocardial infarction (MI) and to mediate long-standing fibrosis with chronic disease. Myofibroblasts remain a poorly defined cell type in terms of their origins and functional effects in vivo . Here we generate Postn (periostin) gene-targeted mice containing a tamoxifen-inducible Cre for cellular lineage-tracing analysis. This Postn allele identifies essentially all myofibroblasts within the heart and multiple other tissues. Lineage tracing with four additional Cre-expressing mouse lines shows that periostin-expressing myofibroblasts in the heart derive from tissue-resident fibroblasts of the Tcf21 lineage, but not endothelial, immune/myeloid or smooth muscle cells. Deletion of periostin + myofibroblasts reduces collagen production and scar formation after MI. Periostin-traced myofibroblasts also revert back to a less-activated state upon injury resolution. Our results define the myofibroblast as a periostin-expressing cell type necessary for adaptive healing and fibrosis in the heart, which arises from Tcf21 + tissue-resident fibroblasts. The origin and fate of myofibroblasts, the cells responsible for cardiac remodelling and fibrosis, is controversial. Here the authors show that cardiac myofibroblasts express periostin, derive exclusively from tissue-resident fibroblasts, are necessary for scar formation after injury, and can revert back to a less-activated state upon injury resolution.

If and how the heart regenerates after an injury event is highly debated. c-kit-expressing cardiac progenitor cells have been reported as the primary source for generation of new myocardium after injury. Here we generated two genetic approaches in mice to examine whether endogenous c-kit + cells contribute differentiated cardiomyocytes to the heart during development, with ageing or after injury in adulthood. A complementary DNA encoding either Cre recombinase or a tamoxifen-inducible MerCreMer chimaeric protein was targeted to the Kit locus in mice and then bred with reporter lines to permanently mark cell lineage. Endogenous c-kit + cells did produce new cardiomyocytes within the heart, although at a percentage of approximately 0.03 or less, and if a preponderance towards cellular fusion is considered, the percentage falls to below approximately 0.008. By contrast, c-kit + cells amply generated cardiac endothelial cells. Thus, endogenous c-kit + cells can generate cardiomyocytes within the heart, although probably at a functionally insignificant level. Whether or not endogenous c-kit + cells residing within the heart contribute cardiomyocytes during physiological ageing or after injury remains unknown; here, using an inducible lineage tracing system, the c-kit + lineage is shown to generate cardiomyocytes at very low levels, and, by contrast, contributes substantially to cardiac endothelial cell generation. c-kit a minor player in heart regeneration Endogenous cardiac progenitor cells expressing the tyrosine kinase/proto-oncogene c-kit have been reported as the primary source for generation of new myocardium after injury, but other studies with adult cardiac-resident c-kit + cells have reported the opposite: that these cells cannot generate cardiomyocytes in vivo . Jeffrey Molkentin and colleagues address this question using an inducible lineage tracing system. They find that rates of cardiomyocyte formation from the c-kit + lineage are extremely low, and not of physiological significance. By contrast, c-kit + cells contribute substantially to the production of endothelial cells in the heart.

Mitochondrial calcium ( m Ca 2+ ) has a central role in both metabolic regulation and cell death signalling, however its role in homeostatic function and disease is controversial 1 . Slc8b1 encodes the mitochondrial Na + /Ca 2+ exchanger (NCLX), which is proposed to be the primary mechanism for m Ca 2+ extrusion in excitable cells 2 , 3 . Here we show that tamoxifen-induced deletion of Slc8b1 in adult mouse hearts causes sudden death, with less than 13% of affected mice surviving after 14 days. Lethality correlated with severe myocardial dysfunction and fulminant heart failure. Mechanistically, cardiac pathology was attributed to m Ca 2+ overload driving increased generation of superoxide and necrotic cell death, which was rescued by genetic inhibition of mitochondrial permeability transition pore activation. Corroborating these findings, overexpression of NCLX in the mouse heart by conditional transgenesis had the beneficial effect of augmenting m Ca 2+ clearance, preventing permeability transition and protecting against ischaemia-induced cardiomyocyte necrosis and heart failure. These results demonstrate the essential nature of m Ca 2+ efflux in cellular function and suggest that augmenting m Ca 2+ efflux may be a viable therapeutic strategy in disease. Conditional deletion of the mitochondrial Na + /Ca 2+ exchanger NCLX in adult mouse hearts causes sudden death due to mitochondrial calcium overload, whereas its overexpression limits cell death elicited by ischaemia reperfusion injury and heart failure. Homeostasis 'chalked up' to mitochondrial calcium exchange The relevance of mitochondrial calcium exchange in vivo has been controversial. Here, John Elrod and colleagues explore the physiological significance of this process in the mouse heart. Conditional deletion of the mitochondrial sodium–calcium exchanger NCLX in adult mouse hearts caused sudden death owing to mitochondrial calcium overload and necrotic cell death. Conversely, overexpression of NCLX in mouse hearts limited cell death caused by ischaemia reperfusion injury, the tissue damage caused when blood rushes back to a site that has suffered a lack of oxygen. The authors conclude that cardiomyocyte mitochondrial calcium exchange is a prominent mitochondrial regulatory mechanism in cardiac disease.

The mechanisms that promote the generation of new coronary vasculature during cardiac homeostasis and after injury remain a fundamental and clinically important area of study in the cardiovascular field. Recently, it was reported that mesenchymal-to-endothelial transition (MEndoT) contributes to substantial numbers of coronary endothelial cells after myocardial infarction. Therefore, the MEndoT has been proposed as a paradigm mediating neovascularization and is considered a promising therapeutic target in cardiac regeneration. Here, we show that preexisting endothelial cells mainly beget new coronary vessels in the adult mouse heart, with essentially no contribution from other cell sources through cell-lineage transdifferentiation. Genetic-lineage tracing revealed that cardiac fibroblasts expand substantially after injury, but do not contribute to the formation of new coronary blood vessels, indicating no contribution of MEndoT to neovascularization. Moreover, genetic-lineage tracing with a pulse-chase labeling strategy also showed that essentially all new coronary vessels in the injured heart are derived from preexisting endothelial cells, but not from other cell lineages. These data indicate that therapeutic strategies for inducing neovascularization should not be based on targeting presumptive lineage transdifferentiation such as MEndoT. Instead, preexisting endothelial cells appear more likely to be the therapeutic target for promoting neovascularization and driving heart regeneration after injury.

Pathologic hypertrophy of the heart is regulated through membrane-bound receptors and intracellular signaling pathways that function, in part, by altering Ca²⁺ handling and Ca²⁺-dependent signaling effectors. Transient receptor potential canonical (TRPC) channels are important mediators of Ca²⁺-dependent signal transduction that can sense stretch or activation of membrane-bound receptors. Here we generated cardiac-specific transgenic mice that express dominant-negative (dn) TRPC3, dnTRPC6, or dnTRPC4 toward blocking the activity of the TRPC3/6/7 or TRPC1/4/5 subfamily of channels in the heart. Remarkably, all three dn transgenic strategies attenuated the cardiac hypertrophic response following either neuroendocrine agonist infusion or pressure-overload stimulation. dnTRPC transgenic mice also were partially protected from loss of cardiac functional performance following long-term pressure-overload stimulation. Importantly, adult myocytes isolated from hypertrophic WT hearts showed a unique Ca²⁺ influx activity under store-depleted conditions that was not observed in myocytes from hypertrophied dnTRPC3, dnTRPC6, or dnTRPC4 hearts. Moreover, dnTRPC4 inhibited the activity of the TRPC3/6/7 subfamily in the heart, suggesting that these two subfamilies function in coordinated complexes. Mechanistically, inhibition of TRPC channels in transgenic mice or in cultured neonatal myocytes significantly reduced activity in the calcineurin-nuclear factor of activated T cells (NFAT), a known Ca²⁺-dependent hypertrophy-inducing pathway. Thus, TRPC channels are necessary mediators of pathologic cardiac hypertrophy, in part through a calcineurin-NFAT signaling pathway.

Animals use their muscles to shiver to generate heat when exposed to the cold. But this is a short-term adaptation. Long term, it is believed the body relies on the brown adipose tissue (BAT) to generate heat in a nonshivering fashion. New work from Muthu Periasamy and colleagues challenge this BAT-centric view by showing that the muscle is also a key site of nonshivering thermogenesis. The role of skeletal muscle in nonshivering thermogenesis (NST) is not well understood. Here we show that sarcolipin (Sln), a newly identified regulator of the sarco/endoplasmic reticulum Ca 2+ -ATPase (Serca) pump 1 , 2 , 3 , 4 , 5 , is necessary for muscle-based thermogenesis. When challenged to acute cold (4 °C), Sln −/− mice were not able to maintain their core body temperature (37 °C) and developed hypothermia. Surgical ablation of brown adipose tissue and functional knockdown of Ucp1 allowed us to highlight the role of muscle in NST. Overexpression of Sln in the Sln-null background fully restored muscle-based thermogenesis, suggesting that Sln is the basis for Serca-mediated heat production. We show that ryanodine receptor 1 (Ryr1)-mediated Ca 2+ leak is an important mechanism for Serca-activated heat generation. Here we present data to suggest that Sln can continue to interact with Serca in the presence of Ca 2+ , which can promote uncoupling of the Serca pump and cause futile cycling. We further show that loss of Sln predisposes mice to diet-induced obesity, which suggests that Sln-mediated NST is recruited during metabolic overload. These data collectively suggest that SLN is an important mediator of muscle thermogenesis and whole-body energy metabolism.