Table 2:

Potential therapeutic targets inspired from exercise-induced molecular adaptations in cardiomyocytes

Molecular Mechanism	Approach	Phenotype in preclinical model(s)	Advantages	Disadvantages	References
Heart-secreted mediators of cell-cell communication	Natriuretic peptide agonism (Sacubitril-Valsartan: neprilysin treatment in conjunction with angiotensin receptor blocker)	Favorable remodeling, improved contractility, survival benefit in humans with HF of multiple etiologies	Oral medication, FDA approved for HF in humans as first-line therapy	Potentially limiting anti-hypertensive actions in some patients; cardiomyocyte specific effects not completely elucidated	^{61,64–66,223}
	GDF15 antagonism (GFRAL receptor neutralizing monoclonal antibody)	Improved cardiac function, reduced adipose and muscle wasting in mouse model of HF due to ER stress and radiation exposure	Human monoclonal antibody with demonstrated efficacy for cancer cachexia	Unclear effects on cardiomyocyte/cardiac adaptations to exercise; repeat dosing required	⁸⁷
	NRG-1 mimetic (ErB4 activating small molecule)	Improved cardiac function and reduced fibrosis in mouse models of MI and doxorubicin cardiotoxicity	Increased tissue specificity due to receptor specificity	Limited effect in cardiac injury models using male mice; need for frequent dosing	¹⁰⁰
Intracellular signaling	IGF-1/PI3K/Akt Pathway Activation (IGF1 tethered nanofiber)	Improved cardiac function, cardiomyogenesis, increased capillary density, and reduced apoptosis in rat model of MI	Local activity at site of cardiac injury; cardiomyogenic potential	Administration only studied at infarct zone; Unclear long-term effects	²²⁴
Transcriptional regulation	CITED4 gene transfer (intravenous delivery of AAV9-cTnT-CITED4 in mice)	Physiological cardiomyocyte hypertrophy; Reduced cardiomyocyte apoptosis, inflammation, fibrosis, and dysfunction in IRI model	Cardiomyocyte specific delivery; long-term gene expression; Low immunogenicity	Dose-dependent off-target effects; Possible time-dependent reduction in transgene expression; Cost	¹⁷⁶
	ERR activation (pan-ERR agonists SLU-PP-32 and SLU-PP-915)	Improved mitochondrial function, FA oxidation, cardiac function in mice with TAC induced HF; No improvement in pathological hypertrophy	Potential effects in other ERR-responsive organs (skeletal muscle); Systemic delivery without genetic modifications	Limited efficacy in preclinical models for adaptations beyond mitochondrial function; Potential off-target effects across tissues; Unclear dose scaling and frequency for efficacy in larger animal models	^177,225
	PGC-1a activation through AMPK or Sirtuin activation (AICAR, Resveratrol, SRT2104)	Improved cardiac contractility, mitochondrial function, cardiac function, and decreased oxidative stress in aged mice (26-28 months); improved cardiac function and mitochondrial function in diabetic cardiomyopathy mouse model	Reduced ischemia-reperfusion and improved anti-oxidant activity	Risk of chronic activation-induced catabolism, cardiac and systemic dysfunction; limited tissue specificity; unclear long-term safety; need for continuous dosing	^226–229
	YAP/TAZ activation (Hippo inhibitor XMU-MP-1)	Improved cardiac function and pathological hypertrophy, reduced cardiomyocyte apoptosis and fibrosis in mice 3 weeks after TAC	Non-genetic manipulation	Potential off-target increase in extra-cardiac cell proliferation (liver, small intestinal epithelium), lack of long-term safety evaluation, need for continuous dosing	²³⁰
Post-transcriptional regulation	lncExACT1 inhibitor (locked nucleic acid [LNA]-GapmeR)	Increased physiological hypertrophy, cardiomyogenesis, improved fibrosis, improved cardiac function in mice	High specificity of target, enhanced stability through LNA modifications including nuclease resistance, potential to target otherwise difficult-to-drug pathway (ncRNAs)	Unclear efficiency of cardiac vs. extra-cardiac uptake, potential off-target tissue effects, need for continuous dosing	²²