TY - JOUR
T1 - A coordinated multiorgan metabolic response contributes to human mitochondrial myopathy
AU - Southwell, Nneka
AU - Primiano, Guido Alessandro
AU - Nadkarni, Viraj
AU - Attarwala, Nabeel
AU - Beattie, Emelie
AU - Miller, Dawson
AU - Alam, Sumaitaah
AU - Liparulo, Irene
AU - Shurubor, Yevgeniya I
AU - Valentino, Maria Lucia
AU - Carelli, Valerio
AU - Servidei, Serenella
AU - Gross, Steven S
AU - Manfredi, Giovanni
AU - Chen, Qiuying
AU - D'Aurelio, Marilena
PY - 2023
Y1 - 2023
N2 - Mitochondrial diseases are a heterogeneous group of monogenic disorders that result from impaired oxidative phosphorylation (OXPHOS). As neuromuscular tissues are highly energy-dependent, mitochondrial diseases often affect skeletal muscle. Although genetic and bioenergetic causes of OXPHOS impairment in human mitochondrial myopathies are well established, there is a limited understanding of metabolic drivers of muscle degeneration. This knowledge gap contributes to the lack of effective treatments for these disorders. Here, we discovered fundamental muscle metabolic remodeling mechanisms shared by mitochondrial disease patients and a mouse model of mitochondrial myopathy. This metabolic remodeling is triggered by a starvation-like response that evokes accelerated oxidation of amino acids through a truncated Krebs cycle. While initially adaptive, this response evolves in an integrated multiorgan catabolic signaling, lipid store mobilization, and intramuscular lipid accumulation. We show that this multiorgan feed-forward metabolic response involves leptin and glucocorticoid signaling. This study elucidates systemic metabolic dyshomeostasis mechanisms that underlie human mitochondrial myopathies and identifies potential new targets for metabolic intervention.
AB - Mitochondrial diseases are a heterogeneous group of monogenic disorders that result from impaired oxidative phosphorylation (OXPHOS). As neuromuscular tissues are highly energy-dependent, mitochondrial diseases often affect skeletal muscle. Although genetic and bioenergetic causes of OXPHOS impairment in human mitochondrial myopathies are well established, there is a limited understanding of metabolic drivers of muscle degeneration. This knowledge gap contributes to the lack of effective treatments for these disorders. Here, we discovered fundamental muscle metabolic remodeling mechanisms shared by mitochondrial disease patients and a mouse model of mitochondrial myopathy. This metabolic remodeling is triggered by a starvation-like response that evokes accelerated oxidation of amino acids through a truncated Krebs cycle. While initially adaptive, this response evolves in an integrated multiorgan catabolic signaling, lipid store mobilization, and intramuscular lipid accumulation. We show that this multiorgan feed-forward metabolic response involves leptin and glucocorticoid signaling. This study elucidates systemic metabolic dyshomeostasis mechanisms that underlie human mitochondrial myopathies and identifies potential new targets for metabolic intervention.
KW - amino acid metabolism
KW - glucocorticoids
KW - leptin
KW - mitochondrial myopathy
KW - muscle wasting
KW - amino acid metabolism
KW - glucocorticoids
KW - leptin
KW - mitochondrial myopathy
KW - muscle wasting
UR - http://hdl.handle.net/10807/300744
U2 - 10.15252/emmm.202216951
DO - 10.15252/emmm.202216951
M3 - Article
SN - 1757-4676
VL - 15
SP - N/A-N/A
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
ER -