title: Diminished force production and mitochondrial respiratory deficits are strain-dependent myopathies of subacute limb ischemia.
abstract: Reduced skeletal muscle mitochondrial function might be a contributing mechanism to the myopathy and activity based limitations that typically plague patients with peripheral arterial disease (PAD). We hypothesized that mitochondrial dysfunction, myofiber atrophy, and muscle contractile deficits are inherently determined by the genetic background of regenerating ischemic mouse skeletal muscle, similar to how patient genetics affect the distribution of disease severity with clinical PAD.
  
  
  
  Genetically ischemia protected (C57BL/6) and susceptible (BALB/c) mice underwent either unilateral subacute hind limb ischemia (SLI) or myotoxic injury (cardiotoxin) for 28 days. Limbs were monitored for blood flow and tissue oxygen saturation and tissue was collected for the assessment of histology, muscle contractile force, gene expression, mitochondrial content, and respiratory function.
  
  
  
  Despite similar tissue O2saturation and mitochondrial content between strains, BALB/c mice suffered persistent ischemic myofiber atrophy (55.3% of C57BL/6) and muscle contractile deficits (approximately 25% of C57BL/6 across multiple stimulation frequencies). SLI also reduced BALB/c mitochondrial respiratory capacity, assessed in either isolated mitochondria (58.3% of C57BL/6 at SLI on day (d)7, 59.1% of C57BL/6 at SLI d28 across multiple conditions) or permeabilized myofibers (38.9% of C57BL/6 at SLI d7; 76.2% of C57BL/6 at SLI d28 across multiple conditions). SLI also resulted in decreased calcium retention capacity (56.0% of C57BL/6) in BALB/c mitochondria. Nonischemic cardiotoxin injury revealed similar recovery of myofiber area, contractile force, mitochondrial respiratory capacity, and calcium retention between strains.
  
  
  
  Ischemia-susceptible BALB/c mice suffered persistent muscle atrophy, impaired muscle function, and mitochondrial respiratory deficits during SLI. Interestingly, parental strain susceptibility to myopathy appears specific to regenerative insults including an ischemic component. Our findings indicate that the functional deficits that plague PAD patients could include mitochondrial respiratory deficits genetically inherent to the regenerating muscle myofibers.
authors.affiliation: Department of Physiology, East Carolina University, Greenville, NC; Diabetes and Obesity Institute, Brody School of Medicine, East Carolina University, Greenville, NC.
authors.forename: Cameron A
authors.initials: CA
authors.lastname: Schmidt
authors.affiliation: Department of Physiology, East Carolina University, Greenville, NC; Diabetes and Obesity Institute, Brody School of Medicine, East Carolina University, Greenville, NC.
authors.forename: Terence E
authors.initials: TE
authors.lastname: Ryan
authors.affiliation: Department of Physiology, East Carolina University, Greenville, NC; Diabetes and Obesity Institute, Brody School of Medicine, East Carolina University, Greenville, NC.
authors.forename: Chien-Te
authors.initials: CT
authors.lastname: Lin
authors.affiliation: Department of Physiology, East Carolina University, Greenville, NC; Diabetes and Obesity Institute, Brody School of Medicine, East Carolina University, Greenville, NC.
authors.forename: Melissa M R
authors.initials: MMR
authors.lastname: Inigo
authors.affiliation: Department of Physiology, East Carolina University, Greenville, NC; Diabetes and Obesity Institute, Brody School of Medicine, East Carolina University, Greenville, NC.
authors.forename: Tom D
authors.initials: TD
authors.lastname: Green
authors.affiliation: Diabetes and Obesity Institute, Brody School of Medicine, East Carolina University, Greenville, NC; Department of Kinesiology, East Carolina University, Greenville, NC.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Brault
authors.affiliation: Department of Physiology, East Carolina University, Greenville, NC; Diabetes and Obesity Institute, Brody School of Medicine, East Carolina University, Greenville, NC.
authors.forename: Espen E
authors.initials: EE
authors.lastname: Spangenburg
authors.affiliation: Department of Physiology, East Carolina University, Greenville, NC; Diabetes and Obesity Institute, Brody School of Medicine, East Carolina University, Greenville, NC. Electronic address: mcclungj@ecu.edu.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: McClung
mesh_terms: D000818:Animals; D019069:Cell Respiration; D004195:Disease Models, Animal; D005838:Genotype; D006614:Hindlimb; D007511:Ischemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008931:Mitochondria, Muscle / Q000378:metabolism* / Q000473:pathology; D009119:Muscle Contraction; D024510:Muscle Development; D053580:Muscle Strength; D018482:Muscle, Skeletal / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D009133:Muscular Atrophy / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D010641:Phenotype; D012038:Regeneration; D012039:Regional Blood Flow; D013045:Species Specificity; D013997:Time Factors