Downloaded from2 Pluripotent stem cells (PSCs) are highly proliferative cells characterized by robust metabolic demands to power rapid division. For many years considered a passive component or "passenger" of cell fate determination, cell metabolism is now starting to take center stage as a driver of cell fate outcomes. This review provides an update and analysis of our current understanding of PSC metabolism and its role in self-renewal, differentiation, and somatic cell reprogramming to pluripotency. Moreover, we present evidence on the active roles metabolism plays in shaping the epigenome to influence patterns of gene expression that may model key features of early embryonic development.Most investigators view metabolism, which encompasses the synthesis and utilization of macromolecules and energy, as a passive supporter of self-renewal and rapid proliferation in pluripotent stem cells (PSCs) 1 and their differentiated, slower dividing progeny. However, exciting recent studies are changing this perception by showing an active role for metabolism in PSC fate determination.

BackgroundDuchenne muscular dystrophy is a fatal cardiac and skeletal muscle disease resulting from mutations in the dystrophin gene. We have previously demonstrated that a dystrophin‐associated protein, sarcospan (SSPN), ameliorated Duchenne muscular dystrophy skeletal muscle degeneration by activating compensatory pathways that regulate muscle cell adhesion (laminin‐binding) to the extracellular matrix. Conversely, loss of SSPN destabilized skeletal muscle adhesion, hampered muscle regeneration, and reduced force properties. Given the importance of SSPN to skeletal muscle, we investigated the consequences of SSPN ablation in cardiac muscle and determined whether overexpression of SSPN into mdx mice ameliorates cardiac disease symptoms associated with Duchenne muscular dystrophy cardiomyopathy.Methods and Results SSPN‐null mice exhibited cardiac enlargement, exacerbated cardiomyocyte hypertrophy, and increased fibrosis in response to β‐adrenergic challenge (isoproterenol; 0.8 mg/day per 2 weeks). Biochemical analysis of SSPN‐null cardiac muscle revealed reduced sarcolemma localization of many proteins with a known role in cardiomyopathy pathogenesis: dystrophin, the sarcoglycans (α‐, δ‐, and γ‐subunits), and β1D integrin. Transgenic overexpression of SSPN in Duchenne muscular dystrophy mice (mdx TG) improved cardiomyofiber cell adhesion, sarcolemma integrity, cardiac functional parameters, as well as increased expression of compensatory transmembrane proteins that mediate attachment to the extracellular matrix.Conclusions SSPN regulates sarcolemmal expression of laminin‐binding complexes that are critical to cardiac muscle function and protects against transient and chronic injury, including inherited cardiomyopathy.

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Sarcospan (SSPN) has an important role in stabilizing sarcolemmal dystrophin- and utrophin-glycoprotein adhesion complexes at the cell membrane. Loss of cell adhesion leads to contraction-induced muscle damage, causing muscle dysfunction and cell death. Recently we have shown a specific role for SSPN in modulating cardiac cell adhesion and physiological function. After transthoracic aortic constriction (TAC), SSPN-null mice transitioned toward failure faster than wild-type (WT) mice. Muscle histology revealed large focal areas of collagen deposition in SSPN-null hearts after TAC compared to WT hearts, suggesting that increased membrane fragility affected cardiomyocyte survival. Our laboratory has shown that SSPN loss reduces sarcolemmal dystrophin levels and associated adhesion complexes in the heart. Whereas, the complete loss of dystrophin leads to development of Duchenne muscular dystrophy (DMD), causing cardiac dysfunction and early mortality. Overexpression of SSPN in DMD mice increased cell adhesion and laminin binding in hearts, leading to improvements in tissue histopathology and increased expression of utrophin, a functional homologue of dystrophin. Examining the restorative potential of SSPN in dystrophic cardiac tissue, led us to query whether compensatory upregulation of SSPN occurs in failing hearts of TAC-treated WT mice. In failing non-DMD hearts, we found that SSPN expression is increased. We have evidence of a chaperone role for SSPN, and its increased expression in the failing heart may contribute to the increased localization of dystrophin and associated glycoprotein complexes at the sarcolemma, which we observed in failing WT hearts compared to untreated controls. The upregulation of cell-stabilizing cell adhesion complexes may compensate for increased wall stress and counter pathological processes that culminate in cardiomyocyte demise, and we are exploring whether naturally increased expression or transgenic overexpression of SSPN in the heart may protect against damage. In summary, we have found that SSPN promotes cardiac function by maintaining cell adhesion and promoting cell survival during disease conditions.