The onset of heart failure is typically preceded by cardiac hypertrophy, a response of the heart to increased workload, a cardiac insult such as a heart attack or genetic mutation. Cardiac hypertrophy is usually characterized by an increase in cardiomyocyte size and thickening of ventricular walls. Initially, such growth is an adaptive response to maintain cardiac function; however, in settings of sustained stress and as time progresses, these changes become maladaptive and the heart ultimately fails. In this review, we discuss the key features of pathological cardiac hypertrophy and the numerous mediators that have been found to be involved in the pathogenesis of cardiac hypertrophy affecting gene transcription, calcium handling, protein synthesis, metabolism, autophagy, oxidative stress and inflammation. We also discuss new mediators including signaling proteins, microRNAs, long noncoding RNAs and new findings related to the role of calcineurin and calcium-/calmodulin-dependent protein kinases. We also highlight mediators and processes which contribute to the transition from adaptive cardiac remodeling to maladaptive remodeling and heart failure. Treatment strategies for heart failure commonly include diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers and β-blockers; however, mortality rates remain high. Here, we discuss new therapeutic approaches (e.g., RNA-based therapies, dietary supplementation, small molecules) either entering clinical trials or in preclinical development. Finally, we address the challenges that remain in translating these discoveries to new and approved therapies for heart failure.

Pathophysiology of cardiac hypertrophy and heart failure: signaling pathways and novel therapeutic targets.

Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder caused by mutations in the dystrophin gene that result in the absence of the membrane-stabilizing protein dystrophin Dystrophin-deficient muscle fibres are fragile and susceptible to an influx of Ca(2+), which activates inflammatory and muscle degenerative pathways At present there is no cure for DMD, and existing therapies are ineffective Here we show that increasing the expression of intramuscular heat shock protein 72 (Hsp72) preserves muscle strength and ameliorates the dystrophic pathology in two mouse models of muscular dystrophy Treatment with BGP-15 (a pharmacological inducer of Hsp72 currently in clinical trials for diabetes) improved muscle architecture, strength and contractile function in severely affected diaphragm muscles in mdx dystrophic mice In dko mice, a phenocopy of DMD that results in severe spinal curvature (kyphosis), muscle weakness and premature death, BGP-15 decreased kyphosis, improved the dystrophic pathophysiology in limb and diaphragm muscles and extended lifespan We found that the sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA, the main protein responsible for the removal of intracellular Ca(2+)) is dysfunctional in severely affected muscles of mdx and dko mice, and that Hsp72 interacts with SERCA to preserve its function under conditions of stress, ultimately contributing to the decreased muscle degeneration seen with Hsp72 upregulation Treatment with BGP-15 similarly increased SERCA activity in dystrophic skeletal muscles Our results provide evidence that increasing the expression of Hsp72 in muscle (through the administration of BGP-15) has significant therapeutic potential for DMD and related conditions, either as a self-contained therapy or as an adjuvant with other potential treatments, including gene, cell and pharmacological therapies

Hsp72 preserves muscle function and slows progression of severe muscular dystrophy

Over-nutrition in females causes altered fetal growth during pregnancy and permanently programs the metabolism of offspring; however, the temporal and mechanistic origins of these changes, and whether they are reversible, are unknown. We now show that, in obese female mice, cumulus-oocyte complexes exhibit endoplasmic reticulum (ER) stress, high levels of intracellular lipid, spindle abnormalities and reduced PTX3 extracellular matrix protein production. Ovulated oocytes from obese mice contain normal levels of mitochondrial (mt) DNA but have reduced mitochondrial membrane potential and high levels of autophagy compared with oocytes from lean mice. After in vitro fertilization, the oocytes of obese female mice demonstrate reduced developmental potential and form blastocysts with reduced levels of mtDNA. Blastocysts transferred to normal weight surrogates that were then analyzed at E14.5 showed that oocytes from obese mice gave rise to fetuses that were heavier than controls and had reduced liver and kidney mtDNA content per cell, indicating that maternal obesity before conception had altered the transmission of mitochondria to offspring. Treatment of the obese females with the ER stress inhibitor salubrinal or the chaperone inducer BGP-15 before ovulation increased the amount of the mitochondrial replication factors TFAM and DRP1, and mtDNA content in oocytes. Salubrinal and BGP-15 also completely restored oocyte quality, embryo development and the mtDNA content of fetal tissue to levels equivalent to those derived from lean mice. These results demonstrate that obesity before conception imparts a legacy of mitochondrial loss in offspring that is caused by ER stress and is reversible during the final stages of oocyte development and maturation.

/pdf/mitochondrial-dysfunction-in-oocytes-of-obese-mothers-31snisjnrw.pdf

Mitochondrial dysfunction in oocytes of obese mothers: transmission to offspring and reversal by pharmacological endoplasmic reticulum stress inhibitors

Insulin resistance and type 2 diabetes mellitus are associated with mitochondrial dysfunction, and promoting healthy mitochondrial function could benefit patients. This Review discusses novel molecular targets for therapies that enhance mitochondrial function, with an emphasis on nonpharmacological regulation of factors such as nutrition, exercise, temperature and circadian rhythm.

/pdf/skeletal-muscle-mitochondria-as-a-target-to-prevent-or-treat-28asxi7h68.pdf

Skeletal muscle mitochondria as a target to prevent or treat type 2 diabetes mellitus

Induction of heat shock protein (HSP)72 protects against obesity-induced insulin resistance, but the underlying mechanisms are unknown. Here, we show that HSP72 plays a pivotal role in increasing skeletal muscle mitochondrial number and oxidative metabolism. Mice overexpressing HSP72 in skeletal muscle (HSP72Tg) and control wild-type (WT) mice were fed either a chow or high-fat diet (HFD). Despite a similar energy intake when HSP72Tg mice were compared with WT mice, the HFD increased body weight, intramuscular lipid accumulation (triacylglycerol and diacylglycerol but not ceramide), and severe glucose intolerance in WT mice alone. Whole-body VO2, fatty acid oxidation, and endurance running capacity were markedly increased in HSP72Tg mice. Moreover, HSP72Tg mice exhibited an increase in mitochondrial number. In addition, the HSP72 coinducer BGP-15, currently in human clinical trials for type 2 diabetes, also increased mitochondrial number and insulin sensitivity in a rat model of type 2 diabetes. Together, these data identify a novel role for activation of HSP72 in skeletal muscle. Thus, the increased oxidative metabolism associated with activation of HSP72 has potential clinical implications not only for type 2 diabetes but also for other disorders where mitochondrial function is compromised.

https://diabetes.diabetesjournals.org/content/diabetes/63/6/1881.full.pdf

Activating HSP72 in Rodent Skeletal Muscle Increases Mitochondrial Number and Oxidative Capacity and Decreases Insulin Resistance

Beneficial effect of the insulin sensitizer (HSP inducer) BGP-15 on olanzapine-induced metabolic disorders

The regulation of energy metabolism — Bone metabolic activity connection is gender-specific

The efficacy and safety of the new drug, BGP-15, were compared with placebo in insulin-resistant patients in a 28-day dose-ranging study. Forty-seven nondiabetic patients with impaired glucose tolerance were randomly assigned to 4 weeks of treatment with 200 or 400 mg of BGP-15 or placebo. Insulin resistance was determined by hyperinsulinemic euglycemic clamp technique and homeostasis model assessment method, and beta-cell function was measured by intravenous glucose tolerance test. Each BGP-15 dose significantly increased whole body insulin sensitivity (M-1, p=0.032), total body glucose utilization (M-2, p=0.035), muscle tissue glucose utilization (M-3, p=0.040), and fat-free body mass glucose utilization (M-4, p=0.038) compared to baseline and placebo. No adverse drug effects were observed during treatment. BGP-15 at 200 or 400 mg significantly improved insulin sensitivity in insulin-resistant, nondiabetic patients during treatment compared to placebo and was safe and well-tolerated. This was the first clinical study demonstrating the insulin-sensitizing effect of a molecule, which is considered as a co-inducer of heat shock proteins.

Improvement of Insulin Sensitivity by a Novel Drug, BGP-15, in Insulin-resistant Patients: A Proof of Concept Randomized Double-blind Clinical Trial

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Beneficial effect of the insulin sensitizer (HSP inducer) BGP-15 on olanzapine-induced metabolic disorders

The regulation of energy metabolism — Bone metabolic activity connection is gender-specific

Improvement of Insulin Sensitivity by a Novel Drug, BGP-15, in Insulin-resistant Patients: A Proof of Concept Randomized Double-blind Clinical Trial