PGC-1α overexpression partially rescues impaired oxidative and contractile pathophysiology following volumetric muscle loss injury

Southern, William M.; Nichenko, Anna S.; Tehrani, Kayvan Forouhesh; McGranahan, Melissa J.; Krishnan, Laxminarayanan; Qualls, Anita; Jenkins, Nathan T.; Mortensen, Luke J.; Yin, Hang; Yin, Amelia; Guldberg, Robert E.; Greising, Sarah M.; Call, Jarrod A.

doi:10.1038/s41598-019-40606-6

Cited by 34 publications

(55 citation statements)

References 71 publications

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“…Given mitochondria’s key role in modulating muscle mass 83 , preventing dysfunction of this organelle could represent a major therapeutic target for rescuing muscle loss in ballistic trauma patients. In support, recent data have shown the PGC-1α signalling axis is disrupted in mice with VML, and that forced expression of PGC-1α using transfection partially rescued muscle strength and oxidative muscle function 151 , which reinforces previous data during disuse atrophy 152 . These data highlight, for the first time, how targeting the mitochondria may play a key role in muscle remodelling post VML.…”

Section: Novel Strategies To Promote Muscle Regeneration After Ballissupporting

confidence: 88%

Firearms-related skeletal muscle trauma: pathophysiology and novel approaches for regeneration

et al. 2021

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One major cause of traumatic injury is firearm-related wounds (i.e., ballistic trauma), common in both civilian and military populations, which is increasing in prevalence and has serious long-term health and socioeconomic consequences worldwide. Common primary injuries of ballistic trauma include soft-tissue damage and loss, haemorrhage, bone fracture, and pain. The majority of injuries are of musculoskeletal origin and located in the extremities, such that skeletal muscle offers a major therapeutic target to aid recovery and return to normal daily activities. However, the underlying pathophysiology of skeletal muscle ballistic trauma remains poorly understood, with limited evidence-based treatment options. As such, this review will address the topic of firearm-related skeletal muscle injury and regeneration. We first introduce trauma ballistics and the immediate injury of skeletal muscle, followed by detailed coverage of the underlying biological mechanisms involved in regulating skeletal muscle dysfunction following injury, with a specific focus on the processes of muscle regeneration, muscle wasting and vascular impairments. Finally, we evaluate novel approaches for minimising muscle damage and enhancing muscle regeneration after ballistic trauma, which may have important relevance for primary care in victims of violence.

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Section: Novel Strategies To Promote Muscle Regeneration After Ballissupporting

confidence: 88%

Firearms-related skeletal muscle trauma: pathophysiology and novel approaches for regeneration

et al. 2021

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“…We posit that the sequela of VML injury includes impaired whole-body metabolism due to low physical activity and the loss of skeletal muscle tissue. Previous work in animal models of VML has indicated that skeletal muscle specific oxidative function is impaired following injury [ 15 , 16 ], and that the muscle remaining after VML injury has reduced metabolic plasticity compared to healthy, uninjured muscle in response to rehabilitation [ 17 ]. Dysfunction of skeletal muscle metabolism may impede the endogenous healing process and induce further chronic dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Independent of physical activity, volumetric muscle loss injury in a murine model impairs whole-body metabolism

et al. 2021

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Volumetric muscle loss (VML) injuries result in a non-recoverable loss of muscle tissue and function due to trauma or surgery. Reductions in physical activity increase the risk of metabolic comorbidities over time, and it is likely that VML may reduce whole-body activity. However, these aspects remain uncharacterized following injury. Our goal was to characterize the impact of VML on whole-body physical activity and metabolism, and to further investigate possible muscle-specific metabolic changes. Adult male C57Bl/6J (n = 28) mice underwent a standardized VML injury to the posterior compartment of the hind limb, or served as injury naïve controls. Mice underwent longitudinal evaluation of whole-body physical activity and metabolism in specialized cages up to three times over the course of 8 weeks. At terminal time points of 4- and 8-weeks post-VML in vivo muscle function of the posterior compartment was evaluated. Additionally, the gastrocnemius muscle was collected to understand histological and biochemical changes in the muscle remaining after VML. The VML injury did not alter the physical activity of mice. However, there was a noted reduction in whole-body metabolism and diurnal fluctuations between lipid and carbohydrate oxidation were also reduced, largely driven by lower carbohydrate utilization during active hours. Following VML, muscle-specific changes indicate a decreased proportion of fast (i.e., type IIb and IIx) and a greater proportion of slow (i.e., type I and IIa) fibers. However, there were minimal changes in the capillarity and metabolic biochemical activity properties of the gastrocnemius muscle, suggesting a miss-match in capacity to support the physiologic needs of the fibers. These novel findings indicate that following VML, independent of changes in physical activity, there is whole-body diurnal metabolic inflexibility. Supporting future investigations into the chronic and overlooked co-morbidities of VML injury.

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“…To assess the integrity of mitochondrial biogenesis signaling in KO muscle, 8 additional untreated mice (n = 4 LM; n = 4 KO) underwent a 30 minute in vivo electrical stimulation protocol to simulate an acute bout of exercise as previously described 15 . Briefly, mice were anesthetized with isoflurane (1.5-2.0%) and platinum-iridium needle electrodes were placed around the sciatic nerve.…”

Section: Acute Stimulation Protocolmentioning

confidence: 99%

“…Mitochondrial function was assessed as previously described 15 Mitochondrial respiration was terminated by the addition of cyanide (2 mM).…”

Section: Mitochondrial Assaysmentioning

confidence: 99%

“…iQ SYBR Green Supermix (Bio-Rad) and sequence-specific primers were used to assess mRNA levels for the following genes, PGC-1α, (For: 5'-AGC CGT GAC CAC TGA CAA CGA G-3'; Rev: 5'-GCT GCA TGG TTC TGA GTG CTA AG-3'). Gene expression analysis was carried out by qRT-PCR on a Bio-Rad CFX instrument as previously described 15 . Data were normalized to 18S (For: 5'-TTG ATT AAG TCC CTG CCC TTT GT-3'; Rev: 5'-CGA TCC GAG GGC CTA ACT A-3') and relative gene expression was calculated using the 2 -ΔΔCT method.…”

Section: Gene Expressionmentioning

confidence: 99%

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Mitochondrial dysfunction in skeletal muscle of fukutin deficient mice is resistant to exercise- and AICAR-induced rescue

Southern¹,

Nichenko²,

Qualls³

et al. 2020

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Disruptions in the dystrophin-glycoprotein complex (DGC) are clearly the primary basis underlying various forms of muscular dystrophies and dystroglycanopathies, but the cellular consequences of DGC disruption are still being investigated. Mitochondrial abnormalities are becoming an apparent consequence and contributor to dystrophy disease pathology. Herein, we demonstrate that muscle-specific deletion of the fukutin gene [Myf5/fktn-KO mice (KO)], a model of secondary dystroglycanopathy, results in ~30% lower muscle strength (P<0.001) and 16% lower mitochondrial function (P=0.002) compared to healthy littermate controls (LM). We also observed ~80% lower PGC-1α signaling (P=0.004), a primary transcription factor for mitochondrial biogenesis, in KO mice that likely contributes to the mitochondrial defects. PGC-1α is posttranslationally regulated via phosphorylation by AMPK. Treatment with the AMPK agonist AICAR (5-aminoimidazole-4-carboxamide ribonucleotide) failed to rescue mitochondrial deficits in KO mice (P=0.458) but did have beneficial (~30% greater) effects on recovery of muscle contractility following injury in both LM and KO mice compared to saline treatment (P=0.006).The beneficial effects of AMPK stimulation via AICAR on muscle function may be partially explained by AMPK's other role of regulating skeletal muscle autophagy, a cellular process critical for clearance of damaged and/or dysfunctional organelles. Two primary conclusions can be drawn from this data, 1) fukutin deletion produces intrinsic muscular metabolic defects that likely contribute to dystroglycanopathy disease pathology, and 2) AICAR treatment accelerates recovery of muscle function following injury suggesting AMPK signaling as a possible target for therapeutic strategies.

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PGC-1α overexpression partially rescues impaired oxidative and contractile pathophysiology following volumetric muscle loss injury

Cited by 34 publications

References 71 publications

Firearms-related skeletal muscle trauma: pathophysiology and novel approaches for regeneration

Firearms-related skeletal muscle trauma: pathophysiology and novel approaches for regeneration

Independent of physical activity, volumetric muscle loss injury in a murine model impairs whole-body metabolism

Mitochondrial dysfunction in skeletal muscle of fukutin deficient mice is resistant to exercise- and AICAR-induced rescue

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