A causal role for mitochondrial DNA (mtDNA) mutagenesis in mammalian aging is supported by recent studies demonstrating that the mtDNA mutator mouse, harboring a defect in the proofreading-exonuclease activity of mitochondrial polymerase gamma, exhibits accelerated aging phenotypes characteristic of human aging, systemic mitochondrial dysfunction, multisystem pathology, and reduced lifespan. Epidemiologic studies in humans have demonstrated that endurance training reduces the risk of chronic diseases and extends life expectancy. Whether endurance exercise can attenuate the cumulative systemic decline observed in aging remains elusive. Here we show that 5 mo of endurance exercise induced systemic mitochondrial biogenesis, prevented mtDNA depletion and mutations, increased mitochondrial oxidative capacity and respiratory chain assembly, restored mitochondrial morphology, and blunted pathological levels of apoptosis in multiple tissues of mtDNA mutator mice. These adaptations conferred complete phenotypic protection, reduced multisystem pathology, and prevented premature mortality in these mice. The systemic mitochondrial rejuvenation through endurance exercise promises to be an effective therapeutic approach to mitigating mitochondrial dysfunction in aging and related comorbidities.

Congenital fibrosarcoma (CFS) is a pediatric spindle cell tumor of the soft tissues that usually presents before the age of 2 years. Although these tumors display histologic features of malignancy and frequently recur, they have a relatively good prognosis and only rarely metastasize. CFS must therefore be differentiated from more aggressive spindle cell sarcomas that occur during childhood, particularly adult-type fibrosarcoma (ATFS), which can have an identical morphology. CFS must also be distinguished from benign but cellular fibroblastic lesions of the same age group, including infantile fibromatosis (IFB) and myofibromatosis (MFB). Unfortunately, standard pathologic examination often does not differentiate CFS from these other conditions. The authors recently identified a novel chromosomal translocation in CFS, t(12;15)(p13;q25), which gives rise to an ETV6-NTRK3 gene fusion. They subsequently developed reverse transcription-polymerase chain reaction (RT-PCR) assays that can detect ETV6-NTRK3 fusion transcripts in CFS frozen or paraffin-embedded tumor specimens. To confirm the use of this assay in the differential diagnosis of CFS, they have screened a larger series of childhood pediatric spindle cell lesions for ETV6-NTRK3 gene fusions, including 11 cases of CFS, 13 malignant spindle cell tumors (including ATFS), and 38 benign spindle cell tumors (including IFB and MFB). Of the 11 cases diagnosed as CFS, 10 showed the ETV6-NTRK3 gene fusion, whereas none of the 51 other malignant or benign spindle cell tumors demonstrated this fusion gene. They also compared their RT-PCR findings with those of conventional cytogenetics and with immunohistochemical detection of the ETV6-NTRK3 protein using antisera to NTRK3. They conclude that RT-PCR analysis is superior to these techniques for the detection of the ETV6-NTRK3 gene fusion in pediatric spindle cell tumors, and it is a reliable and specific modality for the diagnosis of CFS.

Unaccustomed exercise is followed by delayed-onset muscle soreness and morphological changes in skeletal muscle. Animal studies have demonstrated that women have an attenuated response to muscle damage. We studied the effect of eccentric exercise in untrained male (n = 8) and female (n = 8) subjects using a unilateral exercise design [exercise (Ex) and control (Con) legs]. Plasma granulocyte counts [before (Pre) and 48 h after exercise (+48h)] and creatine kinase activity [Pre, 24 h after exercise (+24h), +48h, and 6 days after exercise (+6d)] were determined before (Pre) and after (+24h, +48h, +6d) exercise, with biopsies taken from the vastus lateralis of each leg at +48h for determination of muscle damage and/or inflammation. Plasma granulocyte counts increased for men and decreased for women at +48h (P < 0.05), and creatine kinase activity increased for both genders at +48h and +6d (P < 0.01). There were significantly greater areas of both focal (P < 0.001) and extensive (P < 0.01) damage in the Ex vs. Con leg for both genders, which was assessed by using toluidine blue staining. The number of leukocyte common antigen-positive cells/mm(2) tissue increased with exercise (P < 0.05), and men tended to show more in their Ex vs. Con leg compared with women (P = 0.052). Men had a greater total (Ex and Con legs) number of bcl-2-positive cells/mm(2) tissue vs. women (P < 0.05). Atrophic fibers with homogeneous bcl-2-positive staining were seen only in men (n = 3). We conclude that muscle damage is similar between genders, yet the inflammatory response is attenuated in women vs. men. Finally, exercise may stimulate the expression of proteins involved in apoptosis in skeletal muscle.

Massage therapy is commonly used during physical rehabilitation of skeletal muscle to ameliorate pain and promote recovery from injury. Although there is evidence that massage may relieve pain in injured muscle, how massage affects cellular function remains unknown. To assess the effects of massage, we administered either massage therapy or no treatment to separate quadriceps of 11 young male participants after exercise-induced muscle damage. Muscle biopsies were acquired from the quadriceps (vastus lateralis) at baseline, immediately after 10 min of massage treatment, and after a 2.5-hour period of recovery. We found that massage activated the mechanotransduction signaling pathways focal adhesion kinase (FAK) and extracellular signal-regulated kinase 1/2 (ERK1/2), potentiated mitochondrial biogenesis signaling [nuclear peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α)], and mitigated the rise in nuclear factor κB (NFκB) (p65) nuclear accumulation caused by exercise-induced muscle trauma. Moreover, despite having no effect on muscle metabolites (glycogen, lactate), massage attenuated the production of the inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and reduced heat shock protein 27 (HSP27) phosphorylation, thereby mitigating cellular stress resulting from myofiber injury. In summary, when administered to skeletal muscle that has been acutely damaged through exercise, massage therapy appears to be clinically beneficial by reducing inflammation and promoting mitochondrial biogenesis.

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