Abstract
Mitochondrial oxidative metabolism and energy transduction pathways are critical for skeletal and cardiac muscle function. The expression of genes important for mitochondrial biogenesis and oxidative metabolism are under the control of members of the peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1) family of transcriptional coactivators and the estrogen-related receptor (ERR) subfamily of nuclear receptors. Perturbations in PGC-1 and/or ERR activities have been associated with alterations in capacity for endurance exercise, rates of muscle atrophy, and cardiac function. The mechanism(s) by which PGC-1 and ERR proteins regulate muscle-specific transcriptional programs is not fully understood. We show here that PGC-1α and ERRs induce the expression of a so far uncharacterized muscle-specific protein, PGC-1- and ERR-induced regulator in muscle 1 (Perm1), which regulates the expression of selective PGC-1/ERR target genes. Perm1 is required for the basal as well as PGC-1α-enhanced expression of genes with roles in glucose and lipid metabolism, energy transfer, and contractile function. Silencing of Perm1 in cultured myotubes compromises respiratory capacity and diminishes PGC-1α-induced mitochondrial biogenesis. Our findings support a role for Perm1 acting downstream of PGC-1α and ERRs to regulate muscle-specific pathways important for energy metabolism and contractile function. Elucidating the function of Perm1 may enable novel approaches for the treatment of disorders with compromised skeletal muscle bioenergetics, such as mitochondrial myopathies and age-related/disease-associated muscle atrophies.
Highlights
The regulatory mechanisms that control skeletal muscle bioenergetics are not fully understood
PGC-1␣, PGC-1, and estrogen-related receptor (ERR) Induce PGC-1- and ERR-induced regulator in muscle 1 (Perm1) in C2C12 Myotubes—To identify novel proteins that may cooperate with PGC-1␣ and/or mediate the effects of PGC-1␣ in skeletal muscle, we screened for genes that are induced by PGC-1␣ in differentiated C2C12 cells, are expressed selectively in muscle, and encode for so far uncharacterized proteins
Consistent with Perm1 being an ERR target gene, Perm1 was strongly induced by the introduction of ERR and ERR␥ whose endogenous levels are low in C2C12 myotubes (Fig. 1B)
Summary
The regulatory mechanisms that control skeletal muscle bioenergetics are not fully understood. Peroxisome proliferator-activated receptor (PPAR) ␥ coactivator 1␣ (PGC-1␣) and PGC-1 are two members of the PGC-1 family and important regulators of mitochondrial biogenesis and function in cardiac and skeletal muscle [5,6,7,8] They are expressed at high levels in heart and skeletal muscle and can induce mitochondrial biogenesis and oxidative capacity when expressed ectopically in myotubes in vitro and muscle tissue in vivo (9 –14). ERR␣ and the related receptors ERR and ERR␥ are orphan nuclear receptors that act both downstream and parallel to PGC-1 coactivators to control the expression of a broad set of genes important for energy homeostasis, including genes for mitochondrial biogenesis and oxidative function [30, 31]. We show here that PGC-1/ERR-induced regulator in muscle 1 (Perm1) is a muscle-specific gene that is induced by PGC-1␣/ and ERRs and required for the expression of a subset of genes important for muscle mitochondrial biogenesis and oxidative capacity
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