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

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

doi:10.1038/s41598-019-40606-6

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

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

Kinesiology

Research output: Contribution to journal › Article › peer-review

29 Scopus citations

Abstract

Volumetric muscle loss (VML) injury is characterized by a non-recoverable loss of muscle fibers due to ablative surgery or severe orthopaedic trauma, that results in chronic functional impairments of the soft tissue. Currently, the effects of VML on the oxidative capacity and adaptability of the remaining injured muscle are unclear. A better understanding of this pathophysiology could significantly shape how VML-injured patients and clinicians approach regenerative medicine and rehabilitation following injury. Herein, the data indicated that VML-injured muscle has diminished mitochondrial content and function (i.e., oxidative capacity), loss of mitochondrial network organization, and attenuated oxidative adaptations to exercise. However, forced PGC-1α over-expression rescued the deficits in oxidative capacity and muscle strength. This implicates physiological activation of PGC1-α as a limiting factor in VML-injured muscle’s adaptive capacity to exercise and provides a mechanistic target for regenerative rehabilitation approaches to address the skeletal muscle dysfunction.

Original language	English (US)
Article number	4079
Journal	Scientific reports
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41598-019-40606-6
State	Published - Dec 1 2019

Bibliographical note

Funding Information:
This work was supported by funding from: the Alliance for Regenerative Rehabilitation Research & Training (AR3T) awarded to SMG and JAC, which is supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of Neurological Disorders and Stroke (NINDS), and National Institute of Biomedical Imaging and Bioengineering (NIBIB) of the National Institutes of Health under Award Number P2CHD086843; The Assistant Secretary of Defense for Health Affairs endorsed by the Department of Defense, through the Clinical & Rehabilitative Medicine Research Program, FY17 Neuromusculoskeletal Injuries Rehabilitation Research Award (W81XWH-18-1-0710 to SMG and JAC). Opinions, interpretations, conclusions and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense or National Institutes of Health.

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© 2019, The Author(s).

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Southern, W. M., Nichenko, A. S., Tehrani, K. F., McGranahan, M. J., Krishnan, L., Qualls, A. E., Jenkins, N. T., Mortensen, L. J., Yin, H., Yin, A., Guldberg, R. E., Greising, S. M., & Call, J. A. (2019). PGC-1α overexpression partially rescues impaired oxidative and contractile pathophysiology following volumetric muscle loss injury. Scientific reports, 9(1), Article 4079. https://doi.org/10.1038/s41598-019-40606-6

Southern, WM, Nichenko, AS, Tehrani, KF, McGranahan, MJ, Krishnan, L, Qualls, AE, Jenkins, NT, Mortensen, LJ, Yin, H, Yin, A, Guldberg, RE, Greising, SM & Call, JA 2019, 'PGC-1α overexpression partially rescues impaired oxidative and contractile pathophysiology following volumetric muscle loss injury', Scientific reports, vol. 9, no. 1, 4079. https://doi.org/10.1038/s41598-019-40606-6

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abstract = "Volumetric muscle loss (VML) injury is characterized by a non-recoverable loss of muscle fibers due to ablative surgery or severe orthopaedic trauma, that results in chronic functional impairments of the soft tissue. Currently, the effects of VML on the oxidative capacity and adaptability of the remaining injured muscle are unclear. A better understanding of this pathophysiology could significantly shape how VML-injured patients and clinicians approach regenerative medicine and rehabilitation following injury. Herein, the data indicated that VML-injured muscle has diminished mitochondrial content and function (i.e., oxidative capacity), loss of mitochondrial network organization, and attenuated oxidative adaptations to exercise. However, forced PGC-1α over-expression rescued the deficits in oxidative capacity and muscle strength. This implicates physiological activation of PGC1-α as a limiting factor in VML-injured muscle{\textquoteright}s adaptive capacity to exercise and provides a mechanistic target for regenerative rehabilitation approaches to address the skeletal muscle dysfunction.",

author = "Southern, {William M.} and Nichenko, {Anna S.} and Tehrani, {Kayvan F.} and McGranahan, {Melissa J.} and Laxminarayanan Krishnan and Qualls, {Anita E.} and Jenkins, {Nathan T.} and Mortensen, {Luke J.} and Hang Yin and Amelia Yin and Guldberg, {Robert E.} and Greising, {Sarah M.} and Call, {Jarrod A.}",

note = "Funding Information: This work was supported by funding from: the Alliance for Regenerative Rehabilitation Research & Training (AR3T) awarded to SMG and JAC, which is supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of Neurological Disorders and Stroke (NINDS), and National Institute of Biomedical Imaging and Bioengineering (NIBIB) of the National Institutes of Health under Award Number P2CHD086843; The Assistant Secretary of Defense for Health Affairs endorsed by the Department of Defense, through the Clinical & Rehabilitative Medicine Research Program, FY17 Neuromusculoskeletal Injuries Rehabilitation Research Award (W81XWH-18-1-0710 to SMG and JAC). Opinions, interpretations, conclusions and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense or National Institutes of Health. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

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AU - Nichenko, Anna S.

AU - Tehrani, Kayvan F.

AU - McGranahan, Melissa J.

AU - Krishnan, Laxminarayanan

AU - Qualls, Anita E.

AU - Jenkins, Nathan T.

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AU - Guldberg, Robert E.

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AU - Call, Jarrod A.

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N2 - Volumetric muscle loss (VML) injury is characterized by a non-recoverable loss of muscle fibers due to ablative surgery or severe orthopaedic trauma, that results in chronic functional impairments of the soft tissue. Currently, the effects of VML on the oxidative capacity and adaptability of the remaining injured muscle are unclear. A better understanding of this pathophysiology could significantly shape how VML-injured patients and clinicians approach regenerative medicine and rehabilitation following injury. Herein, the data indicated that VML-injured muscle has diminished mitochondrial content and function (i.e., oxidative capacity), loss of mitochondrial network organization, and attenuated oxidative adaptations to exercise. However, forced PGC-1α over-expression rescued the deficits in oxidative capacity and muscle strength. This implicates physiological activation of PGC1-α as a limiting factor in VML-injured muscle’s adaptive capacity to exercise and provides a mechanistic target for regenerative rehabilitation approaches to address the skeletal muscle dysfunction.

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

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