Abstract
Compromised muscle mitochondrial metabolism is a hallmark of peripheral arterial disease, especially in patients with the most severe clinical manifestation — critical limb ischemia (CLI). We asked whether inflexibility in metabolism is critical for the development of myopathy in ischemic limb muscles. Using Polg mtDNA mutator (D257A) mice, we reveal remarkable protection from hind limb ischemia (HLI) due to a unique and beneficial adaptive enhancement of glycolytic metabolism and elevated ischemic muscle PFKFB3. Similar to the relationship between mitochondria from CLI and claudicating patient muscles, BALB/c muscle mitochondria are uniquely dysfunctional after HLI onset as compared with the C57BL/6 (BL6) parental strain. AAV-mediated overexpression of PFKFB3 in BALB/c limb muscles improved muscle contractile function and limb blood flow following HLI. Enrichment analysis of RNA sequencing data on muscle from CLI patients revealed a unique deficit in the glucose metabolism Reactome. Muscles from these patients express lower PFKFB3 protein, and their muscle progenitor cells possess decreased glycolytic flux capacity in vitro. Here, we show supplementary glycolytic flux as sufficient to protect against ischemic myopathy in instances where reduced blood flow–related mitochondrial function is compromised preclinically. Additionally, our data reveal reduced glycolytic flux as a common characteristic of the failing CLI patient limb skeletal muscle.
Highlights
Peripheral arterial disease (PAD) is the third leading cause of atherosclerotic cardiovascular mortality [1] and a disease whose global incidence has increased substantially in the last 20 years [2]
A transgenic mouse harboring a mutant allele of mtDNA polymerase γ (D257A, The Jackson Laboratory, stock no. 017341) was subjected to hind limb ischemia (HLI), facilitating the examination of the effects of progressive lifelong mitochondrial dysfunction on ischemic myopathy
While exploring the role of mitochondrial sufficiency in ischemic limb myopathy, this study revealed that enhanced glycolytic metabolism in homozygous aged mtDNA mutator mice provided remarkable protection from ischemic muscle injury in a murine model of PAD
Summary
Peripheral arterial disease (PAD) is the third leading cause of atherosclerotic cardiovascular mortality [1] and a disease whose global incidence has increased substantially in the last 20 years [2]. Metabolic inflexibility culminates in necrotic cell death caused by a decline in cellular ATP, leading to insufficient ATP-dependent ion pump activity within the cell membrane and swelling of the cell On this basis, the clinical importance of metabolic health is highlighted by the fact that necrotic lesions and nonhealing ulcers are the primary causes of limb amputation in critical limb ischemia (CLI) patients. Published [3,4,5,6,7] data suggest that mitochondrial-derived disruptions in skeletal muscle energy charge are factors in the etiology of, and susceptibility to, preclinical and clinical ischemic myopathy To this end, targeting cell metabolism in the context of PAD is a logical avenue of therapeutic discovery for limb salvage. This is even more pertinent, given the propensity of PAD patients to be aged, suffer from comorbidities (diabetes), make unhealthy lifestyle decisions (smoking, sedentary behavior), and be prescribed medications for other health problems (statins, metformin) with known independent effects on skeletal muscle metabolism [8, 9]
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