Cardiomyocyte Perm1 sustains cardiac bioenergetic reserve and exercise capacity

The PGC-1/ERR axis controls both steady-state mitochondrial respiration and the capacity to expand ATP production on demand, but whether this reserve function requires dedicated downstream effectors, and whether its loss is detectable at rest, remain unclear. We tested whether Perm1, a striated muscle-specific PGC-1/ERR-induced regulator, is required for cardiac bioenergetic reserve.

We generated cardiomyocyte-specific Perm1 knockout mice using constitutive αMHC-nCre and tamoxifen-inducible αMHC-MerCreMer drivers and followed to 12 months and to 4 months after tamoxifen, respectively. Mitochondrial respiration was measured by high-resolution respirometry and ultrastructure by electron microscopy; energetic capacity under load was tested by treadmill exercise with tissue ATP quantification and by β-adrenergic stimulation of neonatal cardiomyocytes.

Perm1 deletion did not perturb cardiac development; neither constitutive nor adult-onset deletion impaired cardiac structure and systolic function through 12 months. Despite this, mitochondrial respiration was reduced by 20-25% without a change in total mitochondrial content or OxPhos subunit abundance. MICOS components MIC60 and MIC19 were selectively reduced, and mitochondria redistributed from subsarcolemmal to interfibrillar compartments. Perm1-deficient mice of both sexes showed ∼50% lower treadmill endurance at 6 and 12 months and failed to maintain cardiac ATP at a submaximal workload, whereas gastrocnemius ATP and plasma lactate were unaffected. β-Adrenergic stimulation raised ATP content in control cardiomyocytes, and Perm1 knockdown blunted this response.

Perm1 is a cardiomyocyte-intrinsic determinant of cardiac bioenergetic reserve: dispensable for resting function but required to expand ATP production when demand rises. This regulation is invisible to resting phenotyping and emerges only under stress.